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Özalp FR, Yörükoğlu K, Çalışkan Yıldırım E, Uzun M, Demirciler E, Semiz HS. Prognostic Value of B7-H3 and a Novel Scoring System in Localized Renal Cell Carcinoma. MEDICINA (KAUNAS, LITHUANIA) 2025; 61:867. [PMID: 40428825 PMCID: PMC12113493 DOI: 10.3390/medicina61050867] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/06/2025] [Revised: 04/29/2025] [Accepted: 05/03/2025] [Indexed: 05/29/2025]
Abstract
Background and Objectives: Renal cell carcinoma (RCC) is a biologically heterogeneous malignancy, and traditional prognostic models often fail to provide accurate risk stratification. B7-H3 (CD276), an immune checkpoint molecule, has been implicated in RCC progression but remains underexplored as a prognostic biomarker. Materials and Methods: This retrospective study analyzed 52 patients with localized RCC who underwent nephrectomy. Immunohistochemical staining was used to assess B7-H3 expression. A novel prognostic scoring system, the Renal Immune Prognostic Index (RIPI), incorporating B7-H3 expression, tumor necrosis, tumor grade, and pathological staging, was developed and validated. Kaplan-Meier survival analysis and Cox proportional hazard models were employed to evaluate disease-free survival (DFS) and overall survival (OS). Results: High B7-H3 expression was significantly associated with shorter DFS (12 vs. 54 months; p = 0.001) and OS (70 vs. 123 months; p = 0.002). The RIPI demonstrated strong prognostic performance, stratifying the patients into distinct risk groups with a C-index of 0.82. The high-risk patients had a median DFS of 14 months, compared with 125 months in the low-risk group (p < 0.001). Conclusions: B7-H3 expression serves as a significant prognostic biomarker in localized RCC, correlating with poorer survival outcomes. The integration of B7-H3 into the RIPI enhances risk stratification by incorporating both molecular and pathological features. These findings support the incorporation of immune biomarkers into clinical practice and highlight B7-H3 as a potential target for novel therapeutic strategies in RCC.
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Affiliation(s)
- Faruk Recep Özalp
- Department of Medical Oncology, Faculty of Medicine, Dokuz Eylul University, 35340 Izmir, Turkey; (E.Ç.Y.); (E.D.); (H.S.S.)
| | - Kutsal Yörükoğlu
- Department of Pathology, Faculty of Medicine, Dokuz Eylul University, 35340 Izmir, Turkey;
| | - Eda Çalışkan Yıldırım
- Department of Medical Oncology, Faculty of Medicine, Dokuz Eylul University, 35340 Izmir, Turkey; (E.Ç.Y.); (E.D.); (H.S.S.)
| | - Mehmet Uzun
- Department of Medical Oncology, Faculty of Medicine, Dokuz Eylul University, 35340 Izmir, Turkey; (E.Ç.Y.); (E.D.); (H.S.S.)
| | - Erkut Demirciler
- Department of Medical Oncology, Faculty of Medicine, Dokuz Eylul University, 35340 Izmir, Turkey; (E.Ç.Y.); (E.D.); (H.S.S.)
| | - Hüseyin Salih Semiz
- Department of Medical Oncology, Faculty of Medicine, Dokuz Eylul University, 35340 Izmir, Turkey; (E.Ç.Y.); (E.D.); (H.S.S.)
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Martínez-Gamboa DA, Hans R, Moreno-Cortes E, Figueroa-Aguirre J, Garcia-Robledo JE, Vargas-Cely F, Booth N, Castro-Martinez DA, Adams RH, Castro JE. CAR T-cell therapy landscape in pediatric, adolescent and young adult oncology - A comprehensive analysis of clinical trials. Crit Rev Oncol Hematol 2025; 209:104648. [PMID: 39900318 DOI: 10.1016/j.critrevonc.2025.104648] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Revised: 01/29/2025] [Accepted: 01/30/2025] [Indexed: 02/05/2025] Open
Abstract
Chimeric Antigen Receptor (CAR) T-cell therapy has emerged as a transformative approach in cancer treatment, particularly for hematologic malignancies. This therapy involves the genetic modification of patients' T-cells to target specific tumor antigens, bypassing the traditional MHC-TCR-mediated recognition. This innovation marks a significant step toward personalized medicine and precision oncology. In the pediatric, adolescent, and young adult (P-AYA) populations, Tisagenlecleucel (Kymriah®) exemplifies the success of CAR T-cell therapy, demonstrating significant efficacy in treating relapsed or refractory acute lymphoblastic leukemia (r/r ALL). However, the development of CAR T-cell therapies for P-AYA patients has not progressed as rapidly as for adults, with only one FDA approval for pediatric applications compared to six for adults up to 2024. Several challenges hinder the development of pediatric CAR T-cell therapies, including complex production logistics, limited clinical site access, restrictive patient eligibility criteria, and financial constraints, necessitating more effective incentives for pediatric oncology drug development independent of adult indications. To assess the current landscape of CAR T-cell therapy in P-AYA oncology, we conducted a comprehensive review of clinical trials registered on ClinicalTrials.gov up to May 2024. Our analysis included 77 trials exclusively targeting the P-AYA population from an initial pool of 40,690 studies filtered by age, dates, and specific criteria related to CAR T-cell interventions in cancer therapy. We found that 45 % of these trials originated from the USA and 30 % from China. The data retrieved from these trials provided insights into various aspects, including histological categories, antigenic targets, CAR-T generations, costimulatory domains, manufacturing processes, geographical distribution, and funding sources. This review highlighted a predominant focus on hematologic malignancies, particularly B-cell acute lymphoblastic leukemia (B-ALL), with significant attention to dual antigen targeting (CD19 and CD22) to address resistance mechanisms. Emerging targets such as GD2 for solid tumors and B7-H3 for various cancers also showed promise. Additionally, most trials still utilize second-generation CAR-T constructs with 4-1BB costimulatory domains, reflecting a conservative approach in pediatric populations. Our findings underscore the disparity in CAR T-cell therapy development between pediatric and adult populations, driven by distinct biological, ethical, and economic considerations. Pediatric cancers require specialized treatments tailored to the unique biology and genetic makeup of pediatric oncology. However, research and drug development have historically focused less on pediatric needs. Despite legislative efforts to promote pediatric oncology drug development, significant gaps remain. Clinical trials for P-AYA populations face challenges in patient enrollment, trial design, and funding, often relying on academic and non-profit institutions. Addressing these barriers is critical for advancing CAR T-cell therapy in pediatric oncology, improving outcomes, and ensuring equitable access to innovative treatments for these vulnerable populations. This review aims to inform future research and policy decisions, promoting advancements in CAR T-cell therapy for P-AYA cancer patients.
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Affiliation(s)
- David A Martínez-Gamboa
- Division of Hematology and Medical Oncology, Mayo Clinic, Phoenix, AZ, USA; Cancer Research and Cellular Therapies Laboratory, Mayo Clinic, Phoenix, AZ, USA.
| | - Rhea Hans
- Division of Hematology and Medical Oncology, Mayo Clinic, Phoenix, AZ, USA; Cancer Research and Cellular Therapies Laboratory, Mayo Clinic, Phoenix, AZ, USA; Center for Cancer and Blood Disorders, Phoenix Children's Hospital, Phoenix, AZ, USA; Bone Marrow Transplant Fellow at Memorial Sloan Kettering Cancer Center, NY, USA
| | - Eider Moreno-Cortes
- Division of Hematology and Medical Oncology, Mayo Clinic, Phoenix, AZ, USA; Cancer Research and Cellular Therapies Laboratory, Mayo Clinic, Phoenix, AZ, USA
| | - Juana Figueroa-Aguirre
- Division of Hematology and Medical Oncology, Mayo Clinic, Phoenix, AZ, USA; Cancer Research and Cellular Therapies Laboratory, Mayo Clinic, Phoenix, AZ, USA
| | - Juan Esteban Garcia-Robledo
- Division of Hematology and Medical Oncology, Mayo Clinic, Phoenix, AZ, USA; Cancer Research and Cellular Therapies Laboratory, Mayo Clinic, Phoenix, AZ, USA
| | - Fabio Vargas-Cely
- Division of Hematology and Medical Oncology, Mayo Clinic, Phoenix, AZ, USA; Cancer Research and Cellular Therapies Laboratory, Mayo Clinic, Phoenix, AZ, USA
| | - Natalie Booth
- Blood and Marrow Transplant Physician in the Cancer and Blood Disorders Institute at Johns Hopkins All Children's Hospital, USA
| | | | - Roberta H Adams
- Division of Hematology and Medical Oncology, Mayo Clinic, Phoenix, AZ, USA; Center for Cancer and Blood Disorders, Phoenix Children's Hospital, Phoenix, AZ, USA
| | - Januario E Castro
- Division of Hematology and Medical Oncology, Mayo Clinic, Phoenix, AZ, USA; Cancer Research and Cellular Therapies Laboratory, Mayo Clinic, Phoenix, AZ, USA
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Wu L, Liang F, Chen C, Zhang Y, Huang H, Pan Y. Identification of prognostic and therapeutic biomarkers associated with macrophage and lipid metabolism in pancreatic cancer. Sci Rep 2025; 15:14584. [PMID: 40281115 PMCID: PMC12032141 DOI: 10.1038/s41598-025-99144-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Accepted: 04/17/2025] [Indexed: 04/29/2025] Open
Abstract
Although macrophages and lipid metabolism significantly influence the progression of various cancers, their precise roles in pancreatic cancer (PC) remain unclear. This study focuses on identifying and validating biomarkers associated with macrophage-related genes (MRGs) and lipid metabolism-related genes (LMRGs), providing new targets and strategies for therapeutic intervention. This research utilized datasets from TCGA-PAAD, GSE62452, and GSE57495. Candidate genes were identified by overlapping differentially expressed genes with MRGs from WGCNA and LMRGs. Regression analyses were performed to pinpoint potential biomarkers and construct a risk model, which underwent evaluation. A nomogram was subsequently developed and validated. Additional analyses, including functional enrichment, somatic mutation profiling, immune landscape assessment, and RT-qPCR, were performed to investigate the underlying biological mechanisms in PC. The study identified ADH1A, ACACB, CD36, CERS4, PDE3B, ALOX5, and CRAT as biomarkers for PC. RT-qPCR results revealed reduced expression of ADH1A, ACACB, CD36, CERS4, PDE3B, and CRAT in tumor samples compared to adjacent tissues, whereas ALOX5 expression was significantly elevated in tumor samples. A risk model utilizing these biomarkers classified PC patients into high- and low-risk cohorts, with high-risk patients showing lower survival probabilities. Subsequently, risk score and N stage were identified as independent prognostic factors, leading to the development of a nomogram. Notably, both risk cohorts showed significant enrichment in the "cell cycle" pathway. Furthermore, TP53 mutations were prevalent in both high-risk (76%) and low-risk (50%) cohorts. Correlation analysis indicated that PVRL2 (an immunosuppressive factor), CD276 (an immunoactivator), and CCL20 (a chemotactic factor) had the highest positive correlation with the risk score. In this study, ADH1A, ACACB, CD36, CERS4, PDE3B, ALOX5, and CRAT were identified as biomarkers for PC, with their expression levels validated in clinical samples. These findings offered a potential theoretical foundation for developing targeted treatments for PC.
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Affiliation(s)
- Lili Wu
- Department of Surgical Nursing, Fujian Medical University Union Hospital, Fuzhou, People's Republic of China
| | - Feihong Liang
- Department of General Surgery, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Fuzhou, 350001, People's Republic of China
- The Cancer Center, Fujian Medical University Union Hospital, Fuzhou, People's Republic of China
| | - Changgan Chen
- Department of General Surgery, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Fuzhou, 350001, People's Republic of China
| | - Yaxin Zhang
- Department of General Surgery, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Fuzhou, 350001, People's Republic of China
| | - Heguang Huang
- Department of General Surgery, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Fuzhou, 350001, People's Republic of China
| | - Yu Pan
- Department of General Surgery, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Fuzhou, 350001, People's Republic of China.
- Central Laboratory, Fujian Medical University Union Hospital, Fuzhou, People's Republic of China.
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Mielcarska S, Kot A, Kula A, Dawidowicz M, Sobków P, Kłaczka D, Waniczek D, Świętochowska E. B7H3 in Gastrointestinal Tumors: Role in Immune Modulation and Cancer Progression: A Review of the Literature. Cells 2025; 14:530. [PMID: 40214484 PMCID: PMC11988818 DOI: 10.3390/cells14070530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2025] [Revised: 03/29/2025] [Accepted: 03/31/2025] [Indexed: 04/14/2025] Open
Abstract
B7-H3 (CD276), a member of the B7 immune checkpoint family, plays a critical role in modulating immune responses and has emerged as a promising target in cancer therapy. It is highly expressed in various malignancies, where it promotes tumor evasion from T cell surveillance and contributes to cancer progression, metastasis, and therapeutic resistance, showing a correlation with the poor prognosis of patients. Although its receptors were not fully identified, B7-H3 signaling involves key intracellular pathways, including JAK/STAT, NF-κB, PI3K/Akt, and MAPK, driving processes crucial for supporting tumor growth such as cell proliferation, invasion, and apoptosis inhibition. Beyond immune modulation, B7-H3 influences cancer cell metabolism, angiogenesis, and epithelial-to-mesenchymal transition, further exacerbating tumor aggressiveness. The development of B7-H3-targeting therapies, including monoclonal antibodies, antibody-drug conjugates, and CAR-T cells, offers promising avenues for treatment. This review provides an up-to-date summary of the B7H3 mechanisms of action, putative receptors, and ongoing clinical trials evaluating therapies targeting B7H3, focusing on the molecule's role in gastrointestinal tumors.
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Affiliation(s)
- Sylwia Mielcarska
- Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, 41-800 Zabrze, Poland; (A.K.); (P.S.); (D.K.)
| | - Anna Kot
- Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, 41-800 Zabrze, Poland; (A.K.); (P.S.); (D.K.)
| | - Agnieszka Kula
- Department of Oncological Surgery, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 40-514 Katowice, Poland; (A.K.); (M.D.); (D.W.)
| | - Miriam Dawidowicz
- Department of Oncological Surgery, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 40-514 Katowice, Poland; (A.K.); (M.D.); (D.W.)
| | - Piotr Sobków
- Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, 41-800 Zabrze, Poland; (A.K.); (P.S.); (D.K.)
| | - Daria Kłaczka
- Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, 41-800 Zabrze, Poland; (A.K.); (P.S.); (D.K.)
| | - Dariusz Waniczek
- Department of Oncological Surgery, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 40-514 Katowice, Poland; (A.K.); (M.D.); (D.W.)
| | - Elżbieta Świętochowska
- Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, 41-800 Zabrze, Poland; (A.K.); (P.S.); (D.K.)
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Guo Y, Wang X, Zhang C, Chen W, Fu Y, Yu Y, Chen Y, Shao T, Zhang J, Ding G. Tumor Immunotherapy Targeting B7-H3: From Mechanisms to Clinical Applications. Immunotargets Ther 2025; 14:291-320. [PMID: 40171330 PMCID: PMC11960814 DOI: 10.2147/itt.s507522] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Accepted: 03/16/2025] [Indexed: 04/03/2025] Open
Abstract
B7-H3 (CD276) is an immune checkpoint from the B7 family of molecules and is abnormally expressed in tumor cells as a co-inhibitory molecule to promote tumor progression. Within the tumor microenvironment (TME), B7-H3 promotes tumor progression by impairing the T cell response, driving the polarization of tumor-associated macrophages (TAMs) to M2 phenotype, and inhibiting the function of other immune cells. In addition, B7-H3 promotes tumor cell proliferation, migration, invasion, metabolism disorder, angiogenesis, and resistance to treatment to promote tumor progression through its non-immunological functions. Immunotherapy targeting B7-H3, as well as combinations with other immune checkpoint therapies, have shown certain efficacy. In this review, we synthesizes the expression of B7-H3 and its mechanism to promote tumor progression through inducing immunomodulation and non-immunological functions, as well as its role of B7-H3 in tumor therapy, aiming to provide a reference for the clinical treatment of tumors.
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Affiliation(s)
- Yining Guo
- College of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, People’s Republic of China
- Department of Urology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, People’s Republic of China
| | - Xudong Wang
- Department of Urology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, People’s Republic of China
| | - Chen Zhang
- Department of Urology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, People’s Republic of China
| | - Weiwu Chen
- Department of Urology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, People’s Republic of China
| | - Yutian Fu
- Department of Urology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, People’s Republic of China
| | - Yanlan Yu
- Department of Urology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, People’s Republic of China
| | - Yicheng Chen
- Department of Urology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, People’s Republic of China
| | - Tiejuan Shao
- College of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, People’s Republic of China
| | - Jie Zhang
- Department of Urology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, People’s Republic of China
| | - Guoqing Ding
- Department of Urology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, People’s Republic of China
- National Engineering Research Center of Innovation and Application of Minimally Invasive Instruments, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310028, People’s Republic of China
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Mielcarska S, Kula A, Dawidowicz M, Waniczek D, Świętochowska E. Prognostic Significance of B7H3 Expression in Solid Tumors: A Systematic Review and Meta-Analysis. Int J Mol Sci 2025; 26:3044. [PMID: 40243697 PMCID: PMC11988431 DOI: 10.3390/ijms26073044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2025] [Revised: 03/07/2025] [Accepted: 03/24/2025] [Indexed: 04/18/2025] Open
Abstract
B7H3 (CD276), an immunoregulatory molecule known for its role in immune evasion by transmitting inhibitory signals to T lymphocytes, has garnered significant attention in recent years as a promising target for cancer immunotherapy. This interest is largely due to its high expression in various types of solid tumors, coupled with low protein levels in normal tissues. However, studies examining the impact of B7H3 on survival outcomes have shown inconsistent results, leaving its prognostic significance not fully clarified. Therefore, this meta-analysis aimed to assess the relationship between B7H3 expression and various prognostic parameters in patients with solid malignancies. PubMed, Web of Science (WOS), Cochrane, SCOPUS, and Embase databases were searched for eligible articles published until November 2024. Statistical analysis was performed using R studio (version 4.3.2). The analysis included a total of 51 eligible studies comprising 11,135 patients. Results showed that overexpression of B7H3 is a negative predictor for all examined survival outcomes: OS (HR = 1.71, 95% CI = 1.44-2.03, p < 0.0001), DFS (HR = 2.02, 95% CI = 1.49-2.73, p < 0.0001), PFS (HR = 2.10, 95% CI = 1.44-3.06, p < 0.0001), RFS (HR = 1.66, 95% CI = 1.11-2.48, p = 0.01), and DSS (HR = 1.70, 95% CI = 1.24-2.32, p < 0.01). Despite the high heterogeneity observed across the studies, the sensitivity analysis confirmed the robustness of these results. This research suggests that B7H3 may serve as an effective biomarker for prognosis in solid tumors.
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Affiliation(s)
- Sylwia Mielcarska
- Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, 19 Jordana St., 41-800 Zabrze, Poland
| | - Agnieszka Kula
- Department of Oncological Surgery, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 41-514 Katowice, Poland; (A.K.); (M.D.); (D.W.)
| | - Miriam Dawidowicz
- Department of Oncological Surgery, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 41-514 Katowice, Poland; (A.K.); (M.D.); (D.W.)
| | - Dariusz Waniczek
- Department of Oncological Surgery, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 41-514 Katowice, Poland; (A.K.); (M.D.); (D.W.)
| | - Elżbieta Świętochowska
- Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, 19 Jordana St., 41-800 Zabrze, Poland
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Özalp FR, Yörükoğlu K, Yıldırım EÇ, Uzun M, Semiz HS. Prognostic value of B7-H3 expression in metastatic renal cell carcinoma and its impact on immunotherapy response. BMC Cancer 2024; 24:1471. [PMID: 39614178 DOI: 10.1186/s12885-024-13238-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Accepted: 11/25/2024] [Indexed: 12/01/2024] Open
Abstract
BACKGROUND Renal cell carcinoma (RCC) is characterised by its immunogenic and proangiogenic nature and its resistance to conventional therapies. The advent of immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) has significantly improved patient survival, but resistance to these treatments remains a challenge. B7-H3, a potential immune checkpoint, has been implicated in modulating the tumour microenvironment and immune escape mechanisms in RCC. METHODS Immunohistochemical analysis of B7-H3 expression was performed in 84 metastatic RCC patients. Tissue microarrays and separate sections of formalin-fixed paraffin-embedded tissue were used for immunohistochemical staining. Membranous staining of the tumor cells was scored and statistical analyses were performed to assess the correlation between B7-H3 expression and treatment outcome. RESULTS B7-H3 expression was absent in 31% of patients, while 33.3% had a score of 1+, 31% had 2+, and 4.8% had 3+. High B7-H3 expression correlated with poorer OS (20 months vs. 45 months, p = 0.012). In patients receiving nivolumab, those with high B7-H3 expression had shorter PFS (2 months vs. 8 months, p = 0.037) and OS (17 months vs. 51 months, p = 0.01). B7-H3 expression was the only factor significantly affecting PFS and OS in multivariate analysis. CONCLUSION High B7-H3 expression is associated with poorer survival outcomes and reduced response to nivolumab in metastatic RCC patients. B7-H3 may serve as a predictive biomarker for immunotherapy response. Future studies should explore targeting B7-H3 in combination with existing therapies to enhance treatment efficacy.
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Affiliation(s)
- Faruk Recep Özalp
- Department of Medical Oncology, Dokuz Eylul University Faculty of Medicine, Izmir, Turkey.
| | - Kutsal Yörükoğlu
- Department of Pathology, Dokuz Eylul University Faculty of Medicine, Izmir, Turkey
| | - Eda Çalışkan Yıldırım
- Department of Medical Oncology, Dokuz Eylul University Faculty of Medicine, Izmir, Turkey
| | - Mehmet Uzun
- Department of Medical Oncology, Dokuz Eylul University Faculty of Medicine, Izmir, Turkey
| | - Hüseyin Salih Semiz
- Department of Medical Oncology, Dokuz Eylul University Faculty of Medicine, Izmir, Turkey
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Theocharopoulos C, Ziogas IA, Douligeris CC, Efstathiou A, Kolorizos E, Ziogas DC, Kontis E. Antibody-drug conjugates for hepato-pancreato-biliary malignancies: "Magic bullets" to the rescue? Cancer Treat Rev 2024; 129:102806. [PMID: 39094332 DOI: 10.1016/j.ctrv.2024.102806] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2024] [Revised: 07/17/2024] [Accepted: 07/28/2024] [Indexed: 08/04/2024]
Abstract
Hepato-Pancreato-Biliary (HPB) malignancies constitute a highly aggressive group of cancers that have a dismal prognosis. Patients not amenable to curative intent surgical resection are managed with systemic chemotherapy which, however, confers little survival benefit. Antibody-Drug Conjugates (ADCs) are tripartite compounds that merge the intricate selectivity and specificity of monoclonal antibodies with the cytodestructive potency of attached supertoxic payloads. In view of the unmet need for drugs that will enhance the survival rates of HPB cancer patients, the assessment of ADCs for treating HPB malignancies has become the focus of extensive clinical and preclinical investigation, showing encouraging preliminary results. In the current review, we offer a comprehensive overview of the growing body of evidence on ADC approaches tested for HPB malignancies. Starting from a concise discussion of the functional principles of ADCs, we summarize here all available data from preclinical and clinical studies evaluating ADCs in HPB cancers.
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Affiliation(s)
| | - Ioannis A Ziogas
- Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
| | | | | | | | - Dimitrios C Ziogas
- First Department of Internal Medicine, Laikon General Hospital, School of Medicine, National Kapodistrian University of Athens, Athens 11527, Greece
| | - Elissaios Kontis
- Department of Surgery, Metaxa Cancer Hospital, Piraeus 18537, Greece
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Perovic D, Dusanovic Pjevic M, Perovic V, Grk M, Rasic M, Milickovic M, Mijovic T, Rasic P. B7 homolog 3 in pancreatic cancer. World J Gastroenterol 2024; 30:3654-3667. [PMID: 39193002 PMCID: PMC11346158 DOI: 10.3748/wjg.v30.i31.3654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 07/24/2024] [Accepted: 08/06/2024] [Indexed: 08/13/2024] Open
Abstract
Despite advances in cancer treatment, pancreatic cancer (PC) remains a disease with high mortality rates and poor survival outcomes. The B7 homolog 3 (B7-H3) checkpoint molecule is overexpressed among many malignant tumors, including PC, with low or absent expression in healthy tissues. By modulating various immunological and nonimmunological molecular mechanisms, B7-H3 may influence the progression of PC. However, the impact of B7-H3 on the survival of patients with PC remains a subject of debate. Still, most available scientific data recognize this molecule as a suppressive factor to antitumor immunity in PC. Furthermore, it has been demonstrated that B7-H3 stimulates the migration, invasion, and metastasis of PC cells, and enhances resistance to chemotherapy. In preclinical models of PC, B7-H3-targeting monoclonal antibodies have exerted profound antitumor effects by increasing natural killer cell-mediated antibody-dependent cellular cytotoxicity and delivering radioisotopes and cytotoxic drugs to the tumor site. Finally, PC treatment with B7-H3-targeting antibody-drug conjugates and chimeric antigen receptor T cells is being tested in clinical studies. This review provides a comprehensive analysis of all PC-related studies in the context of B7-H3 and points to deficiencies in the current data that should be overcome by future research.
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Affiliation(s)
- Dijana Perovic
- Institute of Human Genetics, Faculty of Medicine, University of Belgrade, Belgrade 11000, Serbia
| | - Marija Dusanovic Pjevic
- Institute of Human Genetics, Faculty of Medicine, University of Belgrade, Belgrade 11000, Serbia
| | - Vladimir Perovic
- Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Belgrade 11000, Serbia
| | - Milka Grk
- Institute of Human Genetics, Faculty of Medicine, University of Belgrade, Belgrade 11000, Serbia
| | - Milica Rasic
- Institute of Human Genetics, Faculty of Medicine, University of Belgrade, Belgrade 11000, Serbia
| | - Maja Milickovic
- Department of Abdominal Surgery, Mother and Child Health Care Institute of Serbia “Dr. Vukan Cupic”, Belgrade 11000, Serbia
- Faculty of Medicine, University of Belgrade, Belgrade 11000, Serbia
| | - Tanja Mijovic
- Department of Abdominal Surgery, Mother and Child Health Care Institute of Serbia “Dr. Vukan Cupic”, Belgrade 11000, Serbia
| | - Petar Rasic
- Department of Abdominal Surgery, Mother and Child Health Care Institute of Serbia “Dr. Vukan Cupic”, Belgrade 11000, Serbia
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10
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Zhang ZY, Xu JH, Zhang JL, Lin YX, Ou-Yang J. Pro-cancer role of CD276 as a novel biomarker for clear cell renal cell carcinoma. Urol Oncol 2024; 42:247.e1-247.e10. [PMID: 38600002 DOI: 10.1016/j.urolonc.2024.03.018] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 03/21/2024] [Accepted: 03/28/2024] [Indexed: 04/12/2024]
Abstract
OBJECTIVE Renal cell carcinoma (RCC) is a common malignant tumor with a high incidence in males and the elderly, and clear cell RCC (ccRCC) is the most common RCC subtype. ccRCC is highly metastatic with a poor prognosis. Therefore, it is crucial to obtain a detailed understanding of the molecular mechanism of ccRCC and to identify suitable biomarkers to realize early diagnosis and improve prognosis. METHODS We analyzed data from the Cancer Genome Atlas, investigated the overall differential expression of CD276 in ccRCC, and evaluated the influence of CD276 on patient survival and prognosis. We also performed gene set enrichment analysis (GSEA) and pathway enrichment analysis and investigated cell infiltration and drug responsiveness to further assess the regulatory effect of CD276 on ccRCC. Furthermore, we verified CD276 expression in RCC cell lines and control cell lines. RESULTS The CD276 expression level in ccRCC samples was higher than that in corresponding samples adjacent to the tumors. Moreover, high CD276 expression levels were positively correlated with poor prognosis in patients with RCC. GSEA revealed that CD276 was significantly involved in immune-related pathways, and the level of CD276 expression was confirmed as associated with immune cell infiltration to some extent. Notably, some drugs were predicted to act on CD276, and this was confirmed by molecular docking. Furthermore, high levels of CD276 expression in RCC cell lines were verified. CONCLUSION CD276 expression was significantly increased in ccRCC tissues and cells and positively correlated with patient prognosis. CD276 is a potential prognostic biomarker of ccRCC. Overall, this study provides a potential therapeutic strategy for ccRCC.
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Affiliation(s)
- Zhi-Yu Zhang
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou 215000, Jiangsu, China
| | - Jian-Hao Xu
- Department of Pathology, The First People's Hospital of Kunshan, Suzhou 215300, Jiangsu, China
| | - Jiang-Lei Zhang
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou 215000, Jiangsu, China
| | - Yu-Xin Lin
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou 215000, Jiangsu, China
| | - Jun Ou-Yang
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou 215000, Jiangsu, China.
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11
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Deng T, Deng Y, Tsao ST, Xiong Q, Yao Y, Liu C, Gu MY, Huang F, Wang H. Rapidly-manufactured CD276 CAR-T cells exhibit enhanced persistence and efficacy in pancreatic cancer. J Transl Med 2024; 22:633. [PMID: 38978106 PMCID: PMC11229349 DOI: 10.1186/s12967-024-05462-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2024] [Accepted: 07/01/2024] [Indexed: 07/10/2024] Open
Abstract
BACKGROUND Pancreatic cancer is one of the most lethal malignancies and the lack of treatment options makes it more deadly. Chimeric Antigen Receptor T-cell (CAR-T) immunotherapy has revolutionized cancer treatment and made great breakthroughs in treating hematological malignancies, however its success in treating solid cancers remains limited mainly due to the lack of tumor-specific antigens. On the other hand, the prolonged traditional manufacturing process poses challenges, taking 2 to 6 weeks and impacting patient outcomes. CD276 has recently emerged as a potential therapeutic target for anti-solid cancer therapy. Here, we investigated the efficacy of CD276 CAR-T and rapidly-manufactured CAR-T against pancreatic cancer. METHODS In the present study, CD276 CAR-T was prepared by CAR structure carrying 376.96 scFv sequence, CD8 hinge and transmembrane domain, 4-1BB and CD3ζ intracellular domains. Additionally, CD276 rapidly-manufactured CAR-T (named CD276 Dash CAR-T) was innovatively developed by shortening the duration of ex vitro culture to reduce CAR-T manufacturing time. We evaluated the anti-tumor efficacy of CD276 CAR-T and further compared the functional assessment of Dash CAR-T and conventional CAR-T in vitro and in vivo by detecting the immunophenotypes, killing ability, expansion capacity and tumor-eradicating effect of CAR-T. RESULTS We found that CD276 was strongly expressed in multiple solid cancer cell lines and that CD276 CAR-T could efficiently kill these solid cancer cells. Moreover, Dash CAR-T was successfully manufactured within 48-72 h and the functional validation was carried out subsequently. In vitro, CD276 Dash CAR-T possessed a less-differentiated phenotype and robust proliferative ability compared to conventional CAR-T. In vivo xenograft mouse model, CD276 Dash CAR-T showed enhanced anti-pancreatic cancer efficacy and T cell expansion. Besides, except for the high-dose group, the body weight of mice was maintained stable, and the state of mice was normal. CONCLUSIONS In this study, we proved CD276 CAR-T exhibited powerful activity against pancreatic cancer cells in vitro and in vivo. More importantly, we demonstrated the manufacturing feasibility, acceptable safety and superior anti-tumor efficacy of CD276 Dash CAR-T generated with reduced time. The results of the above studies indicated that CD276 Dash CAR-T immunotherapy might be a novel and promising strategy for pancreatic cancer treatment.
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Affiliation(s)
- Tian Deng
- Department of Research and Development, Hrain Biotechnology Co., Ltd., 1238 Zhangjiang Road, Pudong New District, Shanghai, China
| | - Yingzhi Deng
- Department of Research and Development, Hrain Biotechnology Co., Ltd., 1238 Zhangjiang Road, Pudong New District, Shanghai, China
| | - Shih-Ting Tsao
- Department of Research and Development, Hrain Biotechnology Co., Ltd., 1238 Zhangjiang Road, Pudong New District, Shanghai, China
| | - Qinghui Xiong
- Department of Research and Development, Hrain Biotechnology Co., Ltd., 1238 Zhangjiang Road, Pudong New District, Shanghai, China
| | - Yue Yao
- Department of Research and Development, Hrain Biotechnology Co., Ltd., 1238 Zhangjiang Road, Pudong New District, Shanghai, China
| | - Cuicui Liu
- Regulatory Affairs Department, Hrain Biotechnology Co., Ltd., 1238 Zhangjiang Road, Pudong New District, Shanghai, China
| | - Ming Yuan Gu
- Department of Research and Development, Hrain Biotechnology Co., Ltd., 1238 Zhangjiang Road, Pudong New District, Shanghai, China
| | - Fei Huang
- Department of Research and Development, Hrain Biotechnology Co., Ltd., 1238 Zhangjiang Road, Pudong New District, Shanghai, China.
| | - Haiying Wang
- Department of Research and Development, Hrain Biotechnology Co., Ltd., 1238 Zhangjiang Road, Pudong New District, Shanghai, China.
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12
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Oroujeni M, Carlqvist M, Ryer E, Orlova A, Tolmachev V, Frejd FY. Comparison of approaches for increasing affinity of affibody molecules for imaging of B7-H3: dimerization and affinity maturation. EJNMMI Radiopharm Chem 2024; 9:30. [PMID: 38625607 PMCID: PMC11021382 DOI: 10.1186/s41181-024-00261-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Accepted: 04/08/2024] [Indexed: 04/17/2024] Open
Abstract
BACKGROUND Radionuclide molecular imaging can be used to visualize the expression levels of molecular targets. Affibody molecules, small and high affinity non-immunoglobulin scaffold-based proteins, have demonstrated promising properties as targeting vectors for radionuclide tumour imaging of different molecular targets. B7-H3 (CD276), an immune checkpoint protein belonging to the B7 family, is overexpressed in different types of human malignancies. Visualization of overexpression of B7-H3 in malignancies enables stratification of patients for personalized therapies. Affinity maturation of anti-B7-H3 Affibody molecules as an approach to improve the binding affinity and targeting properties was recently investigated. In this study, we tested the hypothesis that a dimeric format may be an alternative option to increase the apparent affinity of Affibody molecules to B7-H3 and accordingly improve imaging contrast. RESULTS Two dimeric variants of anti-B7-H3 Affibody molecules were produced (designated ZAC12*-ZAC12*-GGGC and ZAC12*-ZTaq_3-GGGC). Both variants were labelled with Tc-99m (99mTc) and demonstrated specific binding to B7-H3-expressing cells in vitro. [99mTc]Tc-ZAC12*-ZAC12*-GGGC showed subnanomolar affinity (KD1=0.28 ± 0.10 nM, weight = 68%), which was 7.6-fold higher than for [99mTc]Tc-ZAC12*-ZTaq_3-GGGC (KD=2.1 ± 0.9 nM). Head-to-head biodistribution of both dimeric variants of Affibody molecules compared with monomeric affinity matured SYNT-179 (all labelled with 99mTc) in mice bearing B7-H3-expressing SKOV-3 xenografts demonstrates that both dimers have lower tumour uptake and lower tumour-to-organ ratios compared to the SYNT-179 Affibody molecule. CONCLUSION The improved functional affinity by dimerization does not compensate the disadvantage of increased molecular size for imaging purposes.
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Affiliation(s)
- Maryam Oroujeni
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, 751 85, Sweden.
- Affibody AB, Solna, 171 65, Sweden.
| | | | - Eva Ryer
- Affibody AB, Solna, 171 65, Sweden
| | - Anna Orlova
- Department of Medicinal Chemistry, Uppsala University, Uppsala, 751 83, Sweden
| | - Vladimir Tolmachev
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, 751 85, Sweden
| | - Fredrik Y Frejd
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, 751 85, Sweden
- Affibody AB, Solna, 171 65, Sweden
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13
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Chen LC, Yang PC, Chen CY, Chiang SF, Chen TW, Chen WTL, Ke TW, Liang JA, Shiau A, Chao KSC, Huang KCY. Dual Inhibition of B7-H3 and EGFR Overcomes Acquired Chemoresistance in Colon Adenocarcinoma. J Cancer 2024; 15:1750-1761. [PMID: 38370387 PMCID: PMC10869969 DOI: 10.7150/jca.91089] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Accepted: 01/18/2024] [Indexed: 02/20/2024] Open
Abstract
Despite advances in therapeutic strategies for colorectal cancer (CRC), CRC has a high disease incidence with significant morbidity and mortality worldwide. Notably, immunotherapy has shown limited efficacy in treating metastatic CRC, underscoring the need for alternative immunotherapeutic targets for the management of metastatic colorectal cancer (mCRC). In the present study, we evaluated the levels of the immune checkpoint proteins PD-L1, PD-L2 and B7-H3 in a large cohort retrospective study. We found that tumor B7-H3 (52.7%) was highly expressed in primary tumors compared to that in PD-L1 (33.6%) or PD-L2 (34.0%). Elevated B7-H3 expression was associated with advanced stage and the risk of distant metastasis and correlated with poor disease-free survival (DFS), suggesting that tumor B7-H3 was an independent prognostic factor associated with worse DFS in colon adenocarcinoma patients (COAD), especially high-risk COAD patients who received adjuvant chemotherapy. Furthermore, we found that B7-H3 significantly promoted cell proliferation and tumor growth in CRC. B7-H3 may stabilize EGFR to activate its downstream pathway for cancer cell proliferation and resistance to oxaliplatin (OXP). Dual targeting of B7-H3 and EGFR markedly rescued the susceptibility to chemotherapy in colorectal cancer cells in vitro and in vivo. Overall, these results showed that B7-H3 exhibited a high prevalence in COAD patients and was significantly associated with worse prognosis in COAD patients. Dual targeting of B7-H3 and EGFR signaling might be a potential therapeutic strategy for high-risk COAD patients.
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Affiliation(s)
- Liang-Chi Chen
- Department of Pathology, China Medical University Hospital, China Medical University, Taichung 40402, Taiwan
| | - Pei-Chen Yang
- Proton Therapy and Science Center, China Medical University Hospital, China Medical University, Taichung 40402, Taiwan
| | - Chia-Yi Chen
- Proton Therapy and Science Center, China Medical University Hospital, China Medical University, Taichung 40402, Taiwan
| | - Shu-Fen Chiang
- Lab of Precision Medicine, Feng-Yuan Hospital, Ministry of Health and Welfare, Taichung 42055, Taiwan
| | - Tsung-Wei Chen
- Department of Pathology, Asia University Hospital, Asia University, Taichung 41354, Taiwan
| | - William Tzu-Liang Chen
- Department of Colorectal Surgery, China Medical University HsinChu Hospital, China Medical University, HsinChu 302, Taiwan
- Department of Colorectal Surgery, China Medical University Hospital, China Medical University, Taichung 40402, Taiwan
- Department of Surgery, School of Medicine, China Medical University, Taichung 40402, Taiwan
| | - Tao-Wei Ke
- Department of Colorectal Surgery, China Medical University Hospital, China Medical University, Taichung 40402, Taiwan
- School of Chinese Medicine, China Medical University, Taichung 40402, Taiwan
| | - Ji-An Liang
- Department of Radiation Oncology, China Medical University Hospital, China Medical University, Taichung, Taiwan
- Department of Radiotherapy, School of Medicine, China Medical University, Taichung 40402, Taiwan
| | - An‑Cheng Shiau
- Department of Radiation Oncology, China Medical University Hospital, China Medical University, Taichung, Taiwan
- Department of Biomedical Imaging and Radiological Science, China Medical University, Taichung 40402, Taiwan
| | - K. S. Clifford Chao
- Proton Therapy and Science Center, China Medical University Hospital, China Medical University, Taichung 40402, Taiwan
- Department of Radiation Oncology, China Medical University Hospital, China Medical University, Taichung, Taiwan
- Department of Radiotherapy, School of Medicine, China Medical University, Taichung 40402, Taiwan
| | - Kevin Chih-Yang Huang
- Department of Biomedical Imaging and Radiological Science, China Medical University, Taichung 40402, Taiwan
- Translation Research Core, China Medical University Hospital, China Medical University, Taichung 40402, Taiwan
- Cancer Biology and Precision Therapeutics Center, China Medical University, Taichung 40402, Taiwan
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14
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Lutz MS, Wang K, Jung G, Salih H, Hagelstein I. An Fc-modified monoclonal antibody as novel treatment option for pancreatic cancer. Front Immunol 2024; 15:1343929. [PMID: 38322253 PMCID: PMC10845339 DOI: 10.3389/fimmu.2024.1343929] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Accepted: 01/08/2024] [Indexed: 02/08/2024] Open
Abstract
Pancreatic cancer is a highly lethal disease with limited treatment options. Hence, there is a considerable medical need for novel treatment strategies. Monoclonal antibodies (mAbs) have significantly improved cancer therapy, primarily due to their ability to stimulate antibody-dependent cellular cytotoxicity (ADCC), which plays a crucial role in their therapeutic efficacy. As a result, significant effort has been focused on improving this critical function by engineering mAbs with Fc regions that have increased affinity for the Fc receptor CD16 expressed on natural killer (NK) cells, the major cell population that mediates ADCC in humans. Here we report on the preclinical characterization of a mAb directed to the target antigen B7-H3 (CD276) containing an Fc part with the amino acid substitutions S239D/I332E to increase affinity for CD16 (B7-H3-SDIE) for the treatment of pancreatic cancer. B7-H3 (CD276) is highly expressed in many tumor entities, whereas expression on healthy tissues is more limited. Our findings confirm high expression of B7-H3 on pancreatic cancer cells. Furthermore, our study shows that B7-H3-SDIE effectively activates NK cells against pancreatic cancer cells in an antigen-dependent manner, as demonstrated by the analysis of NK cell activation, degranulation and cytokine release. The activation of NK cells resulted in significant tumor cell lysis in both short-term and long-term cytotoxicity assays. In conclusion, B7-H3-SDIE constitutes a promising agent for the treatment of pancreatic cancer.
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Affiliation(s)
- Martina S. Lutz
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tuebingen, Tuebingen, Germany
- Cluster of Excellence iFIT (EXC 2180) “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tuebingen, Tuebingen, Germany
| | - Kevin Wang
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tuebingen, Tuebingen, Germany
| | - Gundram Jung
- Cluster of Excellence iFIT (EXC 2180) “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tuebingen, Tuebingen, Germany
- Department of Immunology, Eberhard Karls Universität Tübingen, Tuebingen, Germany
| | - Helmut R. Salih
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tuebingen, Tuebingen, Germany
- Cluster of Excellence iFIT (EXC 2180) “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tuebingen, Tuebingen, Germany
| | - Ilona Hagelstein
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tuebingen, Tuebingen, Germany
- Cluster of Excellence iFIT (EXC 2180) “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tuebingen, Tuebingen, Germany
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Koumprentziotis IA, Theocharopoulos C, Foteinou D, Angeli E, Anastasopoulou A, Gogas H, Ziogas DC. New Emerging Targets in Cancer Immunotherapy: The Role of B7-H3. Vaccines (Basel) 2024; 12:54. [PMID: 38250867 PMCID: PMC10820813 DOI: 10.3390/vaccines12010054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Revised: 12/28/2023] [Accepted: 12/29/2023] [Indexed: 01/23/2024] Open
Abstract
Immune checkpoints (ICs) are molecules implicated in the fine-tuning of immune response via co-inhibitory or co-stimulatory signals, and serve to secure minimized host damage. Targeting ICs with various therapeutic modalities, including checkpoint inhibitors/monoclonal antibodies (mAbs), antibody-drug conjugates (ADCs), and CAR-T cells has produced remarkable results, especially in immunogenic tumors, setting a paradigm shift in cancer therapeutics through the incorporation of these IC-targeted treatments. However, the large proportion of subjects who experience primary or secondary resistance to available IC-targeted options necessitates further advancements that render immunotherapy beneficial for a larger patient pool with longer duration of response. B7-H3 (B7 Homolog 3 Protein, CD276) is a member of the B7 family of IC proteins that exerts pleiotropic immunomodulatory effects both in physiologic and pathologic contexts. Mounting evidence has demonstrated an aberrant expression of B7-H3 in various solid malignancies, including tumors less sensitive to current immunotherapeutic options, and has associated its expression with advanced disease, worse patient survival and impaired response to IC-based regimens. Anti-B7-H3 agents, including novel mAbs, bispecific antibodies, ADCs, CAR-T cells, and radioimmunotherapy agents, have exhibited encouraging antitumor activity in preclinical models and have recently entered clinical testing for several cancer types. In the present review, we concisely present the functional implications of B7-H3 and discuss the latest evidence regarding its prognostic significance and therapeutic potential in solid malignancies, with emphasis on anti-B7-H3 modalities that are currently evaluated in clinical trial settings. Better understanding of B7-H3 intricate interactions in the tumor microenvironment will expand the oncological utility of anti-B7-H3 agents and further shape their role in cancer therapeutics.
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16
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Xu Q, Zheng J, Su Z, Chen B, Gu S. COL10A1 promotes tumorigenesis by modulating CD276 in pancreatic adenocarcinoma. BMC Gastroenterol 2023; 23:397. [PMID: 37974070 PMCID: PMC10652574 DOI: 10.1186/s12876-023-03045-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Accepted: 11/08/2023] [Indexed: 11/19/2023] Open
Abstract
BACKGROUND Pancreatic adenocarcinoma (PAAD) is a lethal malignant tumour. Further study is needed to determine the molecular mechanism and identify novel biomarkers of PAAD. METHODS Gene expression data from the GSE62165 microarray were analysed with the online software Morpheus to identify differentially expressed genes (DEGs). The STRING database was used to generate a protein‒protein interaction (PPI) network for these DEGs. Hub genes were identified with Cytoscape. COL10A1 expression in PAAD was analysed via the GEPIA database. COL10A1 expression in pancreatic cancer cell lines was measured by using qRT‒PCR. The LinkedOmics database was utilized to perform survival analysis of pancreatic adenocarcinoma patients grouped based on COL10A1 expression level. CCK-8, wound healing, and Transwell assays were used to study the role of COL10A1 in pancreatic cancer cell viability, migration, and invasion. Differentially expressed genes that were related to COL10A1 in PAAD were analysed via the LinkedOmics portal. After COL10A1 was knocked down, CD276 expression was assessed by western blotting. RESULTS COL10A1 was identified as one of the hub genes in PAAD by bioinformatics analysis of the GSE62165 microarray with Morpheus, the STRING database and Cytoscape. GEPIA revealed elevated expression of COL10A1 in PAAD samples vs. normal samples. COL10A1 expression was also increased in pancreatic cancer cells vs. control cells. Survival analysis of PAAD patients via LinkedOmics revealed that high expression of COL10A1 was associated with a poorer prognosis. Knockdown of COL10A1 inhibited the proliferation, migration, and invasion of cells in functional assays. Furthermore, mechanistic studies indicated that CD276 was a target of COL10A1 and that knockdown of COL10A1 decreased CD276 expression. Overexpression of CD276 in cells reversed COL10A1 knockdown-induced repression of proliferation and migration. CONCLUSIONS Our research suggests that COL10A1 promotes pancreatic adenocarcinoma tumorigenesis by regulating CD276. This study provides new insight into biomarkers and possible targets for pancreatic cancer treatment.
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Affiliation(s)
- Qiaodong Xu
- Department of Hepatobiliary surgery, Cancer Hospital of Shantou University Medical College, No. 7 Raoping Road, Shantou, 515041, China
| | - Jieting Zheng
- Department of pharmacy, Cancer Hospital of Shantou University Medical College, No. 7 Raoping Road, Shantou, 515041, China
| | - Zegeng Su
- Department of anesthesiology, Cancer Hospital of Shantou University Medical College, No. 7 Raoping Road, Shantou, 515041, China
| | - Binlie Chen
- Department of Hepatobiliary surgery, Cancer Hospital of Shantou University Medical College, No. 7 Raoping Road, Shantou, 515041, China
| | - Songgang Gu
- Department of Hepatobiliary surgery, Cancer Hospital of Shantou University Medical College, No. 7 Raoping Road, Shantou, 515041, China.
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17
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Oroujeni M, Bezverkhniaia EA, Xu T, Liu Y, Plotnikov EV, Klint S, Ryer E, Karlberg I, Orlova A, Frejd FY, Tolmachev V. Evaluation of affinity matured Affibody molecules for imaging of the immune checkpoint protein B7-H3. Nucl Med Biol 2023; 124-125:108384. [PMID: 37699299 DOI: 10.1016/j.nucmedbio.2023.108384] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 08/25/2023] [Accepted: 08/30/2023] [Indexed: 09/14/2023]
Abstract
B7-H3 (CD276), an immune checkpoint protein, is a promising molecular target for immune therapy of malignant tumours. Sufficient B7-H3 expression level is a precondition for successful therapy. Radionuclide molecular imaging is a powerful technique for visualization of expression levels of molecular targets in vivo. Use of small radiolabelled targeting proteins would enable high-contrast radionuclide imaging of molecular targets if adequate binding affinity and specificity of an imaging probe could be provided. Affibody molecules, small engineered affinity proteins based on a non-immunoglobulin scaffold, have demonstrated an appreciable potential in radionuclide imaging. Proof-of principle of radionuclide visualization of expression levels of B7-H3 in vivo was demonstrated using the [99mTc]Tc-AC12-GGGC Affibody molecule. We performed an affinity maturation of AC12, enabling selection of clones with higher affinity. Three most promising clones were expressed with a -GGGC (triglycine-cysteine) chelating sequence at the C-terminus and labelled with technetium-99m (99mTc). 99mTc-labelled conjugates bound to B7-H3-expressing cells specifically in vitro and in vivo. Biodistribution in mice bearing B7-H3-expressing SKOV-3 xenografts demonstrated improved imaging properties of the new conjugates compared with the parental variant [99mTc]Tc-AC12-GGGC. [99mTc]Tc-SYNT-179 provided the strongest improvement of tumour-to-organ ratios. Thus, affinity maturation of B7-H3 Affibody molecules could improve biodistribution and targeting properties for imaging of B7-H3-expressing tumours.
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Affiliation(s)
- Maryam Oroujeni
- Department of Immunology, Genetics and Pathology, Uppsala University, 751 85 Uppsala, Sweden; Affibody AB, 171 65 Solna, Sweden.
| | - Ekaterina A Bezverkhniaia
- Research Centrum for Oncotheranostics, Research School of Chemistry and Applied Biomedical Sciences, Tomsk Polytechnic University, 634050 Tomsk, Russia; Scientific and Research Laboratory of Chemical and Pharmaceutical Research, Siberian State Medical University, Tomsk 634050, Russia; Department of Medicinal Chemistry, Uppsala University, 751 83 Uppsala, Sweden.
| | - Tianqi Xu
- Department of Immunology, Genetics and Pathology, Uppsala University, 751 85 Uppsala, Sweden.
| | - Yongsheng Liu
- Department of Immunology, Genetics and Pathology, Uppsala University, 751 85 Uppsala, Sweden
| | - Evgenii V Plotnikov
- Research Centrum for Oncotheranostics, Research School of Chemistry and Applied Biomedical Sciences, Tomsk Polytechnic University, 634050 Tomsk, Russia
| | | | - Eva Ryer
- Affibody AB, 171 65 Solna, Sweden.
| | | | - Anna Orlova
- Research Centrum for Oncotheranostics, Research School of Chemistry and Applied Biomedical Sciences, Tomsk Polytechnic University, 634050 Tomsk, Russia; Department of Medicinal Chemistry, Uppsala University, 751 83 Uppsala, Sweden.
| | - Fredrik Y Frejd
- Department of Immunology, Genetics and Pathology, Uppsala University, 751 85 Uppsala, Sweden; Affibody AB, 171 65 Solna, Sweden.
| | - Vladimir Tolmachev
- Department of Immunology, Genetics and Pathology, Uppsala University, 751 85 Uppsala, Sweden; Research Centrum for Oncotheranostics, Research School of Chemistry and Applied Biomedical Sciences, Tomsk Polytechnic University, 634050 Tomsk, Russia.
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18
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Rasic P, Jeremic M, Jeremic R, Dusanovic Pjevic M, Rasic M, Djuricic SM, Milickovic M, Vukadin M, Mijovic T, Savic D. Targeting B7-H3-A Novel Strategy for the Design of Anticancer Agents for Extracranial Pediatric Solid Tumors Treatment. Molecules 2023; 28:molecules28083356. [PMID: 37110590 PMCID: PMC10145344 DOI: 10.3390/molecules28083356] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Revised: 04/05/2023] [Accepted: 04/07/2023] [Indexed: 04/29/2023] Open
Abstract
Recent scientific data recognize the B7-H3 checkpoint molecule as a potential target for immunotherapy of pediatric solid tumors (PSTs). B7-H3 is highly expressed in extracranial PSTs such as neuroblastoma, rhabdomyosarcoma, nephroblastoma, osteosarcoma, and Ewing sarcoma, whereas its expression is absent or very low in normal tissues and organs. The influence of B7-H3 on the biological behavior of malignant solid neoplasms of childhood is expressed through different molecular mechanisms, including stimulation of immune evasion and tumor invasion, and cell-cycle disruption. It has been shown that B7-H3 knockdown decreased tumor cell proliferation and migration, suppressed tumor growth, and enhanced anti-tumor immune response in some pediatric solid cancers. Antibody-drug conjugates targeting B7-H3 exhibited profound anti-tumor effects against preclinical models of pediatric solid malignancies. Moreover, B7-H3-targeting chimeric antigen receptor (CAR)-T cells demonstrated significant in vivo activity against different xenograft models of neuroblastoma, Ewing sarcoma, and osteosarcoma. Finally, clinical studies demonstrated the potent anti-tumor activity of B7-H3-targeting antibody-radioimmunoconjugates in metastatic neuroblastoma. This review summarizes the established data from various PST-related studies, including in vitro, in vivo, and clinical research, and explains all the benefits and potential obstacles of targeting B7-H3 by novel immunotherapeutic agents designed to treat malignant extracranial solid tumors of childhood.
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Affiliation(s)
- Petar Rasic
- Department of Abdominal Surgery, Mother and Child Health Care Institute of Serbia "Dr. Vukan Cupic", 11000 Belgrade, Serbia
| | - Marija Jeremic
- Institute of Medical and Clinical Biochemistry, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
| | - Rada Jeremic
- Institute of Medical Physiology "Richard Burian", Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
| | - Marija Dusanovic Pjevic
- Institute of Human Genetics, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
| | - Milica Rasic
- Institute of Human Genetics, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
| | - Slavisa M Djuricic
- Department of Clinical Pathology, Mother and Child Health Care Institute of Serbia "Dr. Vukan Cupic", 11000 Belgrade, Serbia
- Faculty of Medicine, University of Banja Luka, 78000 Banja Luka, Bosnia and Herzegovina
| | - Maja Milickovic
- Department of Abdominal Surgery, Mother and Child Health Care Institute of Serbia "Dr. Vukan Cupic", 11000 Belgrade, Serbia
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
| | - Miroslav Vukadin
- Department of Abdominal Surgery, Mother and Child Health Care Institute of Serbia "Dr. Vukan Cupic", 11000 Belgrade, Serbia
| | - Tanja Mijovic
- Department of Abdominal Surgery, Mother and Child Health Care Institute of Serbia "Dr. Vukan Cupic", 11000 Belgrade, Serbia
| | - Djordje Savic
- Department of Abdominal Surgery, Mother and Child Health Care Institute of Serbia "Dr. Vukan Cupic", 11000 Belgrade, Serbia
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
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19
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Xiao L, Guan X, Xiang M, Wang Q, Long Q, Yue C, Chen L, Liu J, Liao C. B7 family protein glycosylation: Promising novel targets in tumor treatment. Front Immunol 2022; 13:1088560. [PMID: 36561746 PMCID: PMC9763287 DOI: 10.3389/fimmu.2022.1088560] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Accepted: 11/22/2022] [Indexed: 12/12/2022] Open
Abstract
Cancer immunotherapy, including the inhibition of immune checkpoints, improves the tumor immune microenvironment and is an effective tool for cancer therapy. More effective and alternative inhibitory targets are critical for successful immune checkpoint blockade therapy. The interaction of the immunomodulatory ligand B7 family with corresponding receptors induces or inhibits T cell responses by sending co-stimulatory and co-inhibitory signals respectively. Blocking the glycosylation of the B7 family members PD-L1, PD-L2, B7-H3, and B7-H4 inhibited the self-stability and receptor binding of these immune checkpoint proteins, leading to immunosuppression and rapid tumor progression. Therefore, regulation of glycosylation may be the "golden key" to relieve tumor immunosuppression. The exploration of a more precise glycosylation regulation mechanism and glycan structure of B7 family proteins is conducive to the discovery and clinical application of antibodies and small molecule inhibitors.
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Affiliation(s)
- Linlin Xiao
- Department of Orthodontics II, Affiliated Stomatological Hospital of Zunyi Medical University, Zunyi, China,Oral Disease Research Key Laboratory of Guizhou Tertiary Institution, School of Stomatology, Zunyi Medical University, Zunyi, China
| | - Xiaoyan Guan
- Department of Orthodontics II, Affiliated Stomatological Hospital of Zunyi Medical University, Zunyi, China,Oral Disease Research Key Laboratory of Guizhou Tertiary Institution, School of Stomatology, Zunyi Medical University, Zunyi, China
| | - Mingli Xiang
- Department of Orthodontics II, Affiliated Stomatological Hospital of Zunyi Medical University, Zunyi, China,Oral Disease Research Key Laboratory of Guizhou Tertiary Institution, School of Stomatology, Zunyi Medical University, Zunyi, China
| | - Qian Wang
- Oral Disease Research Key Laboratory of Guizhou Tertiary Institution, School of Stomatology, Zunyi Medical University, Zunyi, China
| | - Qian Long
- Department of Orthodontics II, Affiliated Stomatological Hospital of Zunyi Medical University, Zunyi, China,Oral Disease Research Key Laboratory of Guizhou Tertiary Institution, School of Stomatology, Zunyi Medical University, Zunyi, China
| | - Chaoyi Yue
- School of Medicine and Technology, Zunyi Medical University, Zunyi, China
| | - Lulu Chen
- Department of Orthodontics II, Affiliated Stomatological Hospital of Zunyi Medical University, Zunyi, China,Oral Disease Research Key Laboratory of Guizhou Tertiary Institution, School of Stomatology, Zunyi Medical University, Zunyi, China
| | - Jianguo Liu
- Oral Disease Research Key Laboratory of Guizhou Tertiary Institution, School of Stomatology, Zunyi Medical University, Zunyi, China,*Correspondence: Chengcheng Liao, ; Jianguo Liu,
| | - Chengcheng Liao
- Department of Orthodontics II, Affiliated Stomatological Hospital of Zunyi Medical University, Zunyi, China,Oral Disease Research Key Laboratory of Guizhou Tertiary Institution, School of Stomatology, Zunyi Medical University, Zunyi, China,*Correspondence: Chengcheng Liao, ; Jianguo Liu,
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20
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Chen X, Li J, Chen Y, Que Z, Du J, Zhang J. B7 Family Members in Pancreatic Ductal Adenocarcinoma: Attractive Targets for Cancer Immunotherapy. Int J Mol Sci 2022; 23:ijms232315005. [PMID: 36499340 PMCID: PMC9740860 DOI: 10.3390/ijms232315005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 11/25/2022] [Accepted: 11/27/2022] [Indexed: 12/05/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, with a five-year survival rate of approximately 5-10%. The immune checkpoint blockade represented by PD-1/PD-L1 inhibitors has been effective in a variety of solid tumors but has had little clinical response in pancreatic cancer patients. The unique suppressive immune microenvironment is the primary reason for this outcome, and it is essential to identify key targets to remodel the immune microenvironment. Some B7 family immune checkpoints, particularly PD-L1, PD-L2, B7-H3, B7-H4, VISTA and HHLA2, have been identified as playing a significant role in the control of tumor immune responses. This paper provides a comprehensive overview of the recent research progress of some members of the B7 family in pancreatic cancer, which revealed that they can be involved in tumor progression through immune-dependent and non-immune-dependent pathways, highlighting the mechanisms of their involvement in tumor immune escape and assessing the prospects of their clinical application. Targeting B7 family immune checkpoints is expected to result in novel immunotherapeutic treatments for patients with pancreatic cancer.
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Affiliation(s)
- Xin Chen
- Department of Microbiology and Immunology, Medical School, Southeast University, Nanjing 210009, China
- Jiangsu Key Laboratory of Molecular Imaging and Function Imaging, Medical School, Southeast University, Nanjing 210009, China
| | - Jie Li
- Department of Microbiology and Immunology, Medical School, Southeast University, Nanjing 210009, China
| | - Yue Chen
- Department of Microbiology and Immunology, Medical School, Southeast University, Nanjing 210009, China
| | - Ziting Que
- Department of Microbiology and Immunology, Medical School, Southeast University, Nanjing 210009, China
| | - Jiawei Du
- Jiangsu Key Laboratory of Molecular Imaging and Function Imaging, Medical School, Southeast University, Nanjing 210009, China
| | - Jianqiong Zhang
- Department of Microbiology and Immunology, Medical School, Southeast University, Nanjing 210009, China
- Jiangsu Key Laboratory of Molecular Imaging and Function Imaging, Medical School, Southeast University, Nanjing 210009, China
- Correspondence: ; Tel.: +86-25-83272314
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21
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Nguyen TT, Lee HS, Burt BM, Amos CI, Cheng C. A combination of intrinsic and extrinsic features improves prognostic prediction in malignant pleural mesothelioma. Br J Cancer 2022; 127:1691-1700. [PMID: 35999269 PMCID: PMC9596423 DOI: 10.1038/s41416-022-01950-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 08/03/2022] [Accepted: 08/04/2022] [Indexed: 02/01/2023] Open
Abstract
BACKGROUND Malignant pleural mesothelioma (MPM) is a lung pleural cancer with very poor disease outcome. With limited curative MPM treatment available, it is vital to study prognostic biomarkers to categorise different patient risk groups. METHODS We defined gene signatures to separately characterise intrinsic and extrinsic features, and investigated their interactions in MPM tumour samples. Specifically, we calculated gene signature scores to capture the downstream pathways of major mutated driver genes (BAP1, NF2, SETD2 and TP53) as tumour-intrinsic features. Similarly, we inferred the infiltration levels for major immune cells in the tumour microenvironment to characterise tumour-extrinsic features. Lastly, we integrated these features with clinical factors to predict prognosis in MPM. RESULTS The gene signature scores were more prognostic than the corresponding genomic mutations, mRNA and protein expression. High immune infiltration levels were associated with prolonged survival. The integrative model indicated that tumour features provided independent prognostic values than clinical factors and were complementary with each other in survival prediction. CONCLUSIONS By using an integrative model that combines intrinsic and extrinsic features, we can more correctly predict the clinical outcomes of patients with MPM.
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Affiliation(s)
- Thinh T Nguyen
- Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Hyun-Sung Lee
- Division of General Thoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Bryan M Burt
- Division of General Thoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Christopher I Amos
- Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, TX, 77030, USA
- Department of Medicine, Baylor College of Medicine, Houston, TX, 77030, USA
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Chao Cheng
- Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, TX, 77030, USA.
- Department of Medicine, Baylor College of Medicine, Houston, TX, 77030, USA.
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA.
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22
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Xue S, Ge W, Wang K, Mao T, Zhang X, Xu H, Wang Y, Yao J, Li S, Yue M, Ma J, Wang Y, Shentu D, Cui J, Wang L. Association of aging-related genes with prognosis and immune infiltration in pancreatic adenocarcinoma. Front Cell Dev Biol 2022; 10:942225. [PMID: 36003146 PMCID: PMC9393218 DOI: 10.3389/fcell.2022.942225] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Accepted: 06/30/2022] [Indexed: 12/29/2022] Open
Abstract
Pancreatic adenocarcinoma (PAAD) is one of the deadliest malignancies. Aging is described as the degeneration of physiological function, which is complexly correlated with cancer. It is significant to explore the influences of aging-related genes (ARGs) on PAAD. Based on The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) datasets, we used univariate Cox regression analysis and acquired eight differentially expressed ARGs with prognostic values. Two molecular subtypes were identified based on these ARGs to depict PAAD patients’ overall survival (OS) and immune microenvironments preliminarily. Cluster 1 had a poor OS as well as a worse immune microenvironment. Through least absolute shrinkage and selection operator (LASSO) regression analysis, we constructed a seven-ARG risk signature based on the TCGA dataset and verified it in Gene Expression Omnibus (GEO) and International Cancer Genome Consortium (ICGC) to predict the prognoses, immune microenvironments, signal pathways, tumor mutations, and drug sensitivity of PAAD patients. The high-risk group possessed an unfavorable OS compared with that of the low-risk group. We also verified the independence and clinical availability of the risk signature by Cox regression analyses and the establishment of a nomogram, respectively. The higher risk score was associated with several clinical factors such as higher grade and advanced tumor stage as well as lower immunoscore and cluster 1. The negative associations of risk scores with immune, stroma, and estimate scores proved the terrible immune microenvironment in the high-risk group. Relationships between risk score and immune checkpoint gene expression as well as signal pathways provided several therapeutic targets. PAAD patients in the low-risk group possessed lower tumor mutations as well as a higher susceptibility to axitinib and vorinostat. The high-risk group bore a higher TMB and cisplatin and dasatinib may be better options. We used immunohistochemistry and qPCR to confirm the expression of key ARGs with their influences on OS. In conclusion, we identified two ARG-mediated molecular subtypes and a novel seven-ARG risk signature to predict prognoses, immune microenvironments, signal pathways, tumor mutations, and drug sensitivity of PAAD patients.
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Affiliation(s)
- Shengbai Xue
- Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Weiyu Ge
- Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Kexuan Wang
- Department of Nursing, School of Nursing, Xuzhou Medical University, Xuzhou, China
| | - Tiebo Mao
- Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Xiaofei Zhang
- Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Haiyan Xu
- Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Yongchao Wang
- Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Jiayu Yao
- Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Shumin Li
- Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Ming Yue
- Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Jingyu Ma
- Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Yanling Wang
- Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Daiyuan Shentu
- Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Jiujie Cui
- Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
- *Correspondence: Jiujie Cui, ; Liwei Wang,
| | - Liwei Wang
- Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
- *Correspondence: Jiujie Cui, ; Liwei Wang,
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23
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Yang J, Tian Z, Gao H, Xiong F, Cao C, Yu J, Shi W, Zhan Q, Yang C. Clinical significance and correlation of PD-L1, B7-H3, B7-H4, and TILs in pancreatic cancer. BMC Cancer 2022; 22:584. [PMID: 35624419 PMCID: PMC9137118 DOI: 10.1186/s12885-022-09639-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Accepted: 04/28/2022] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND B7 molecules play significant roles in regulating tumor immunity, but their expression patterns and immuno-biological correlations in pancreatic cancer (PaCa) have not been fully discussed. METHODS RNA-sequencing data of B7 molecules of PaCa samples in the Cancer Genome Atlas (TCGA) dataset was downloaded from the UCSC Xena to assess the expression, correlation, and mutation of the B7 family in PaCa. Next, two PaCa tissue microarrays (TMAs, Cat. HPanA150CS02 and HPanA120Su02) were obtained from Outdo BioTech (Shanghai, China). To detect the expression levels of PD-L1, B7-H3 and B7-H4, immunohistochemistry (IHC) staining was performed on these TMAs. RESULTS Most B7 molecules, including B7-1, B7-2, PD-L1, B7-DC, B7-H2, and B7-H5 exhibited similar expression patterns, but B7-H3, B7-H4, B7-H6, and B7-H7 showed outlier expression patterns compared with other B7 molecules. Besides, B7 molecules were genetically stable and exhibited low alteration frequency. IHC staining indicated PD-L1, B7-H3, and B7-H4 were up-regulated in PaCa tissues and showed uncorrelated expression patterns. Furthermore, high expression of PD-L1 and B7-H3 indicated poor-differentiated grades in PaCa. PD-L1 was positively, but B7-H4 was negatively correlated with CD8+ TILs infiltration in PaCa. Moreover, combined PD-L1 and B7-H4 expression was a novel subtyping strategy in PaCa, namely patients with both high PD-L1 and B7-H4 expression exhibited decreased CD8+ TILs infiltration in tumor tissues. CONCLUSION Overall, we systemically analyzed the expression patterns of B7 molecules and proposed a novel subtyping strategy in PaCa. Patients with both high PD-L1 and B7-H4 expression exhibited the immuno-cold phenotype, which may be not suitable for immunotherapy.
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Affiliation(s)
- Jiayue Yang
- Department of Endocrinology, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi, Jiangsu Province, 214023 China
| | - Zhen Tian
- Department of Clinical Laboratory, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi, Jiangsu Province, 214023 China
| | - Han Gao
- Wuxi School of Medicine, Jiangnan University, Wuxi, 214122 China
| | - Fan Xiong
- Department of Endocrinology, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi, Jiangsu Province, 214023 China
| | - Cuiping Cao
- Department of Endocrinology, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi, Jiangsu Province, 214023 China
| | - Jiaojiao Yu
- Department of Endocrinology, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi, Jiangsu Province, 214023 China
| | - Wei Shi
- Department of Endocrinology, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi, Jiangsu Province, 214023 China
| | - Qiang Zhan
- Department of Gastroenterology, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, No. 299 Qing Yang Road, Wuxi, Jiangsu Province, 214023 China
| | - Cheng Yang
- Department of Gastroenterology, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, No. 299 Qing Yang Road, Wuxi, Jiangsu Province, 214023 China
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24
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Deng J, Zhang Q, Lv L, Ma P, Zhang Y, Zhao N, Zhang Y. Identification of an autophagy-related gene signature for predicting prognosis and immune activity in pancreatic adenocarcinoma. Sci Rep 2022; 12:7006. [PMID: 35488119 PMCID: PMC9054801 DOI: 10.1038/s41598-022-11050-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Accepted: 03/10/2022] [Indexed: 12/11/2022] Open
Abstract
Adenocarcinoma of the pancreas (PAAD) is a cancerous growth that deteriorates rapidly and has a poor prognosis. Researchers are investigating autophagy in PAAD to identify a new biomarker and treatment target. An autophagy-related gene (ARG) model for overall survival (OS) was constructed using multivariate Cox regression analyses. A cohort of the Cancer Genome Atlas (TCGA)-PAAD was used as the training group as a basis for model construction. This prediction model was validated with several external datasets. To evaluate model performance, the analysis with receiver operating characteristic curves (ROC) was performed. The Human Protein Atlas (HPA) and Cancer Cell Line Encyclopedia (CCLE) were investigated to validate the effects of ARGs expression on cancer cells. Comparing the levels of immune infiltration between high-risk and low-risk groups was finished through the use of CIBERSORT. The differentially expressed genes (DEGs) between the low-/high-risk groups were analyzed further via Gene Ontology biological process (GO-BP) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, which were used to identify potential small-molecule compounds in Connectivity Map (CMap), followed by half-maximal inhibitory concentration (IC50) examination with PANC-1 cells. The risk score was finally calculated as follows: BAK1 × 0.34 + ITGA3 × 0.38 + BAG3 × 0.35 + APOL1 × 0.26-RAB24 × 0.67519. ITGA3 and RAB24 both emerged as independent prognostic factors in multivariate Cox regression. Each PAAD cohort had a significantly shorter OS in the high-risk group than in the low-risk group. The high-risk group exhibited infiltration of several immune cell types, including naive B cells (p = 0.003), plasma cells (p = 0.044), and CD8 T cells (nearly significant, p = 0.080). Higher infiltration levels of NK cells (p = 0.025), resting macrophages (p = 0.020), and mast cells (p = 0.007) were found in the high-risk group than the low-risk group. The in vitro and in vivo expression of signature ARGs was consistent in the CCLE and HPA databases. The top 3 enriched Gene Ontology biological processes (GO-BPs) were signal release, regulation of transsynaptic signaling, and modulation of chemical synaptic transmission, and the top 3 enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were MAPK, cAMP, and cell adhesion molecules. Four potential small-molecule compounds (piperacetazine, vinburnine, withaferin A and hecogenin) that target ARGs were also identified. Taking the results together, our research shows that the ARG signature may serve as a useful prognostic indicator and reveal potential therapeutic targets in patients with PAAD.
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Affiliation(s)
- Jiang Deng
- Institute of Health Service and Transfusion Medicine, Beijing, 100850, People's Republic of China
- Beijing Key Laboratory of Blood Safety and Supply Technologies, Beijing, 100850, People's Republic of China
| | - Qian Zhang
- Institute of Health Service and Transfusion Medicine, Beijing, 100850, People's Republic of China
- Beijing Key Laboratory of Blood Safety and Supply Technologies, Beijing, 100850, People's Republic of China
| | - Liping Lv
- Institute of Health Service and Transfusion Medicine, Beijing, 100850, People's Republic of China
- Beijing Key Laboratory of Blood Safety and Supply Technologies, Beijing, 100850, People's Republic of China
| | - Ping Ma
- Institute of Health Service and Transfusion Medicine, Beijing, 100850, People's Republic of China
- Beijing Key Laboratory of Blood Safety and Supply Technologies, Beijing, 100850, People's Republic of China
| | - Yangyang Zhang
- Institute of Health Service and Transfusion Medicine, Beijing, 100850, People's Republic of China
- Beijing Key Laboratory of Blood Safety and Supply Technologies, Beijing, 100850, People's Republic of China
| | - Ning Zhao
- Institute of Health Service and Transfusion Medicine, Beijing, 100850, People's Republic of China
- Beijing Key Laboratory of Blood Safety and Supply Technologies, Beijing, 100850, People's Republic of China
| | - Yanyu Zhang
- Institute of Health Service and Transfusion Medicine, Beijing, 100850, People's Republic of China.
- Beijing Key Laboratory of Blood Safety and Supply Technologies, Beijing, 100850, People's Republic of China.
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25
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Zhao B, Huang Z, Zhu X, Cai H, Huang Y, Zhang X, Zhang Z, Lu H, An C, Niu L, Li Z. Clinical Significance of the Expression of Co-Stimulatory Molecule B7-H3 in Papillary Thyroid Carcinoma. Front Cell Dev Biol 2022; 10:819236. [PMID: 35493085 PMCID: PMC9039293 DOI: 10.3389/fcell.2022.819236] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2021] [Accepted: 03/14/2022] [Indexed: 11/13/2022] Open
Abstract
Background: B7-H3, also known as CD276, an important immune checkpoint member of the B7-CD28 family, is confirmed as a promising target after PD-L1 in clinical trials. Although the overexpression of B7-H3 has been associated with invasive metastatic potential and poor prognosis in multiple types of cancer, nothing is known regarding the expression profiles of B7-H3 in papillary thyroid carcinoma (PTC). In this study, we carried out a large-scale analysis of B7-H3 expression in PTC patients and evaluated the potential clinical significance of B7-H3. Methods: In total, data from 1,210 samples, including 867 cases from TCGA and four GEO datasets, were collected for B7-H3–related transcriptome analyses, and 343 postoperative, whole-tumor sections were collected from patients with PTC at our institute for B7-H3–specific immunohistochemistry (IHC) staining. The statistical analysis was primarily accomplished using the R project for statistical computing. Results: B7-H3 positivity was found in 84.8% of PTC patients (291/343), and the mRNA and protein expression levels of B7-H3 in PTC were markedly higher than those of para-tumor tissues (p < 0.001), demonstrating that B7-H3 can serve as a potential diagnostic biomarker for PTC. The significant upregulation of B7-H3 in PTC is caused by distinct patterns of CNVs and CpG DNA methylation. Functional enrichment analysis confirmed that high B7-H3 expression was significantly associated with specific immune features and angiogenesis. High B7-H3 protein expression was associated with tumor size (p = 0.022), extrathyroidal extension (ETE) (p = 0.003), and lymph node metastasis (LNM) (p < 0.001). More importantly, multivariate analysis confirmed that B7-H3 was an independent predictor of relapse-free survival (RFS) (p < 0.05). In the subgroup analysis, positive B7-H3 staining was associated with worse RFS in patients with primary tumor size ≥2 cm (p < 0.05), age ≥55 years (p < 0.05), LNM (p = 0.07), multifocality (p < 0.05), and ETE (p < 0.05). In addition, Circos plots indicated that B7-H3 was significantly associated with other immune checkpoints in the B7-CD28 family. Conclusion: This is the first comprehensive study to elucidate the expression profile of B7-H3 in PTC. Our observations revealed that B7-H3 is a novel independent biomarker for predicting LNM and disease recurrence for PTC patients, and it thus may serve as an indicator that could be used to improve risk-adapted therapeutic strategies and a novel target for immunotherapy strategies for patients who undergo an aggressive disease course.
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Affiliation(s)
- Bohui Zhao
- Department of Head and Neck Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital and Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
| | - Zehao Huang
- Department of Head and Neck Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xinyi Zhu
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Huizhu Cai
- Department of Head and Neck Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yingcheng Huang
- Department of Head and Neck Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiwei Zhang
- Department of Head and Neck Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zongmin Zhang
- Department of Head and Neck Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Haizhen Lu
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- *Correspondence: Haizhen Lu, ; Changming An, ; Lijuan Niu, ; Zhengjiang Li,
| | - Changming An
- Department of Head and Neck Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- *Correspondence: Haizhen Lu, ; Changming An, ; Lijuan Niu, ; Zhengjiang Li,
| | - Lijuan Niu
- Department of Ultrasound, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- *Correspondence: Haizhen Lu, ; Changming An, ; Lijuan Niu, ; Zhengjiang Li,
| | - Zhengjiang Li
- Department of Head and Neck Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- *Correspondence: Haizhen Lu, ; Changming An, ; Lijuan Niu, ; Zhengjiang Li,
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26
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Si S, Wang L, Cao H, Xu Y, Zhan Q. Co-deficiency of B7-H3 and B7-H4 identifies high CD8 + T cell infiltration and better prognosis in pancreatic cancer. BMC Cancer 2022; 22:211. [PMID: 35219310 PMCID: PMC8881843 DOI: 10.1186/s12885-022-09294-w] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Accepted: 02/08/2022] [Indexed: 12/18/2022] Open
Abstract
Background Immunotherapy is a novel hotspot for the treatment of pancreatic adenocarcinoma (PAAD). However, potential biomarkers which could identify the inflamed tumor microenvironment (TME) are urgently required. Methods In the present study, we measured the levels of B7-H3, B7-H4, and major tumor-infiltrating immune cells (TIICs) using bioinformatics analyses and immunohistochemistry (IHC) staining on PAAD samples represented in the tissue microarray (TMA) format. Statistical analysis and figures exhibition were performed using R 4.1.0, SPSS 26.0, and GraphPad Prism 6.0. Results B7-H3 and B7-H4 were up-regulated in PAAD compared with para-tumor tissues, and their expression exhibited no tight correlation in PAAD tissues. B7-H3 and B7-H4 were lowly expressed in well-differentiated PAAD tissues and correlated with poorly differentiated grades. Besides, single B7-H3 or B7-H4 expression exhibited limited prognostic value, but co-deficiency of B7-H3 and B7-H4 predicted a better prognosis in PAAD. Moreover, co-deficiency of B7-H3 and B7-H4 indicated immuno-hot tumors with high CD8 + T cell infiltration. Conclusions Overall, combined B7-H3 and B7-H4 expression is a promising stratification strategy to assess prognosis and immunogenicity in PAAD, which could be used as a novel classifier in clinical practice. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-022-09294-w.
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Xiao Z, Li J, Yu Q, Zhou T, Duan J, Yang Z, Liu C, Xu F. An Inflammatory Response Related Gene Signature Associated with Survival Outcome and Gemcitabine Response in Patients with Pancreatic Ductal Adenocarcinoma. Front Pharmacol 2022; 12:778294. [PMID: 35002712 PMCID: PMC8733666 DOI: 10.3389/fphar.2021.778294] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Accepted: 11/29/2021] [Indexed: 12/12/2022] Open
Abstract
Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive tumors with an extremely low 5-year survival rate. Accumulating evidence has unveiled that inflammatory response promotes tumor progression, enhances angiogenesis, and causes local immunosuppression. Herein, we aim to develop an inflammatory related prognostic signature, and found it could be used to predict gemcitabine response in PDAC. Methods: PDAC cohorts with mRNA expression profiles and clinical information were systematically collected from the four public databases. An inflammatory response related genes (IRRGs) prognostic signature was constructed by LASSO regression analysis. Kaplan–Meier survival analysis, receiver operating characteristic analysis, principal component analysis, and univariate and multivariate Cox analyses were carried out to evaluate effectiveness, and reliability of the signature. The correlation between gemcitabine response and risk score was evaluated in the TCGA-PAAD cohort. The GDSC database, pRRophetic algorithm, and connectivity map analysis were used to predict gemcitabine sensitivity and identify potential drugs for the treatment of PDAC. Finally, we analyzed differences in frequencies of gene mutations, infiltration of immune cells, as well as biological functions between different subgroups divided by the prognostic signature. Results: We established a seven IRRGs (ADM, DCBLD2, EREG, ITGA5, MIF, TREM1, and BTG2) signature which divided the PDAC patients into low- and high-risk groups. Prognostic value of the signature was validated in 11 PDAC cohorts consisting of 1337 PDAC patients from 6 countries. A nomogram that integrated the IRRGs signature and clinicopathologic factors of PDAC patients was constructed. The risk score showed positive correlation with gemcitabine resistance. Two drugs (BMS-536924 and dasatinib) might have potential therapeutic implications in high-risk PDAC patients. We found that the high-risk group had higher frequencies of KRAS, TP53, and CDKN2A mutations, increased infiltration of macrophages M0, neutrophils, and macrophages M2 cells, as well as upregulated hypoxia and glycolysis pathways, while the low-risk group had increased infiltration of CD8+ T, naïve B, and plasma and macrophages M1 cells. Conclusion: We constructed and validated an IRRGs signature that could be used to predict the prognosis and gemcitabine response of patients with PDAC, as well as two drugs (BMS-536924 and dasatinib) may contribute to PDAC treatment.
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Affiliation(s)
- Zhijun Xiao
- Department of Pharmacy, Shanghai University of Medicine and Health Sciences Affiliated Sixth People's Hospital South Campus, Shanghai, China
| | - Jinyin Li
- Department of Pharmacy, Xuhui Central Hospital of Shanghai, Shanghai, China
| | - Qian Yu
- Division of Interventional Radiology, University of Chicago, Chicago, IL, United States
| | - Ting Zhou
- Department of Pharmacy, Shanghai University of Medicine and Health Sciences Affiliated Sixth People's Hospital South Campus, Shanghai, China
| | - Jingjing Duan
- Department of Pharmacy, Shanghai University of Medicine and Health Sciences Affiliated Sixth People's Hospital South Campus, Shanghai, China
| | - Zhen Yang
- Department of Central Laboratory, Shanghai University of Medicine and Health Sciences Affiliated Sixth People's Hospital South Campus, Shanghai, China
| | - Cuicui Liu
- Department of Clinical Laboratory, Shanghai University of Medicine and Health Sciences Affiliated Sixth People's Hospital South Campus, Shanghai, China
| | - Feng Xu
- Department of Pharmacy, Shanghai University of Medicine and Health Sciences Affiliated Sixth People's Hospital South Campus, Shanghai, China.,Department of Pharmacy, Fengxian Hospital, Southern Medical University, Shanghai, China
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28
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Feng R, Chen Y, Liu Y, Zhou Q, Zhang W. The role of B7-H3 in tumors and its potential in clinical application. Int Immunopharmacol 2021; 101:108153. [PMID: 34678689 DOI: 10.1016/j.intimp.2021.108153] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 09/08/2021] [Accepted: 09/08/2021] [Indexed: 02/07/2023]
Abstract
B7-H3 (CD276 molecule) is an immune checkpoint from the B7 family of molecules that acts more as a co-inhibitory molecule to promote tumor progression. It is abnormally expressed on tumor cells and can be induced to express on antigen-presenting cells (APCs) including dendritic cells (DCs) and macrophages. In the tumor microenvironment (TME), B7-H3 promotes tumor progression by impairing T cell response, promoting the polarization of tumor-associated macrophages (TAMs) to M2, inhibiting the function of DCs, and promoting the migration and invasion of cancer-associated fibroblasts (CAFs). In addition, through non-immunological functions, B7-H3 promotes tumor cell proliferation, invasion, metastasis, resistance, angiogenesis, and metabolism, or in the form of exosomes to promote tumor progression. In this process, microRNAs can regulate the expression of B7-H3. B7-H3 may serve as a potential biomarker for tumor diagnosis and a marker of poor prognosis. Immunotherapy targeting B7-H3 and the combination of B7-H3 and other immune checkpoints have shown certain efficacy. In this review, we summarized the basic characteristics of B7-H3 and its mechanism to promote tumor progression by inducing immunosuppression and non-immunological functions, as well as the potential clinical applications of B7-H3 and immunotherapy based on B7-H3.
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Affiliation(s)
- Ranran Feng
- Department of Laboratory Medicine, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Laboratory Medicine, Xiangya School of Medicine, Central South University, Changsha, Hunan, China; Department of Andrology, Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, China
| | - Yong Chen
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Ying Liu
- Department of Laboratory Medicine, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Laboratory Medicine, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Qing Zhou
- Department of Laboratory Medicine, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Laboratory Medicine, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Wenling Zhang
- Department of Laboratory Medicine, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Laboratory Medicine, Xiangya School of Medicine, Central South University, Changsha, Hunan, China.
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Zhang W, Zhang L, Qian J, Lin J, Chen Q, Yuan Q, Zhou J, Zhang T, Shi J, Zhou H. Expression characteristic of 4Ig B7-H3 and 2Ig B7-H3 in acute myeloid leukemia. Bioengineered 2021; 12:11987-12002. [PMID: 34787059 PMCID: PMC8810086 DOI: 10.1080/21655979.2021.2001182] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
Abstract
4IgB7-H3 (4Ig) and 2IgB7-H3 (2Ig) expression characteristics in acute myeloid leukemia (AML) remain unknown. This study investigated mRNA and membrane protein expression of two B7-H3 isoforms in AML cell lines and de novo patients by using RT-PCR and flow cytometry, and analyzed the B7-H3 promoter methylation state by utilizing RQ-MSP. 4Ig was the dominant isoform. 2Ig mRNA expression rate and abundance were elevated in AML in comparison with controls (P = 0.000 and 0.000), while no significant difference in 4Ig (P = 0.802, P = 0.398). Membrane protein levels of B7-H3 isoforms in AML was higher than controls, detected by total B7-H3 expression rate (P = 0.002), total B7-H3 mean fluorescence intensity (MFI) ratio of blast cells and lymphocytes (MFI ratio) (P = 0.000), and 4Ig B7-H3 MFI ratio (P = 0.005). Compared with 2Iglow group, 2Ighigh patients had older age, lower NPM1 mutation, higher FLT3-ITD mutation, and declining complete remission (CR) rates (P = 0.026, 0.012, 0.047, and 0.028). In B7-H3high group, there was a trend toward older age, M4 and M5, worse karyotype, and lower CR rates, although with no marked difference (P > 0.05). The overall survival (OS) of 2Ighigh and B7-H3high groups were shorter than that of 2Iglow and B7-H3low groups in the whole and non-M3 AML cohorts (P = 0.006 and 0.046; P = 0.003 and 0.032). Besides, an unmethylated B7-H3 promoter was identified. In conclusion, 2Ig mRNA and total B7-H3 membrane protein tended to have potential diagnostic value for AML. Specifically, high 2Ig mRNA and total B7-H3 membrane protein expression indicate worse OS. 4Ig and 2Ig expression are methylation-independent.
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Affiliation(s)
- Wei Zhang
- Department of Hematology, The Affiliated Jiangning Hospital with Nanjing Medical University, Nanjing, Jiangsu, China
| | - Lingyi Zhang
- Laboratory Center, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, China.,School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Jun Qian
- Department of Hematology, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Jiang Lin
- Laboratory Center, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Qiaoyun Chen
- Laboratory Center, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Qian Yuan
- Laboratory Center, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Jingdong Zhou
- Department of Hematology, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Tingjuan Zhang
- Laboratory Center, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, China.,School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Jinning Shi
- Department of Hematology, The Affiliated Jiangning Hospital with Nanjing Medical University, Nanjing, Jiangsu, China
| | - Hong Zhou
- School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
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Amori G, Sugawara E, Shigematsu Y, Akiya M, Kunieda J, Yuasa T, Yamamoto S, Yonese J, Takeuchi K, Inamura K. Tumor B7-H3 expression in diagnostic biopsy specimens and survival in patients with metastatic prostate cancer. Prostate Cancer Prostatic Dis 2021; 24:767-774. [PMID: 33558663 DOI: 10.1038/s41391-021-00331-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 01/06/2021] [Accepted: 01/20/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND Prostate cancer spans a broad spectrum from indolent to deadly disease. In the management of prostate cancer, diagnostic biopsy specimens are important sources of data that inform the selection of treatment. B7-H3 (CD276), an immune checkpoint molecule, has emerged as a promising immunotherapy target. B7-H3 expression is related to adverse clinical outcomes in various types of cancer; however, little is known concerning the association between tumor B7-H3 expression in diagnostic biopsy specimens and clinical outcome in patients with metastatic prostate cancer. METHODS We evaluated tumor B7-H3 expression levels in diagnostic biopsy specimens from 135 patients with metastatic prostate cancer and 113 patients with localized prostate cancer. RESULTS High B7-H3 expression was more frequently observed in patients with metastatic cancer than in those with localized cancer (31 vs. 12%; p = 0.0003). In patients with localized cancer, the B7-H3 expression status was not associated with biochemical recurrence-free survival. However, among patients with metastatic cancer, high B7-H3 expression was independently associated with high disease-specific mortality (multivariable hazard ratio [HR] = 2.72; p = 0.047) and overall mortality rates (multivariable HR = 2.04; p = 0.025). CONCLUSIONS Tumor B7-H3 expression in diagnostic biopsy specimens may be a useful biomarker for identifying highly aggressive metastatic prostate cancer. Given the potential utility of anti-B7-H3 immunotherapy, this information may aid in stratifying prostate cancer based on its responsiveness to B7-H3-targeted treatment.
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Affiliation(s)
- Gulanbar Amori
- Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.,Department of Pathology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Emiko Sugawara
- Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.,Department of Pathology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Yasuyuki Shigematsu
- Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.,Department of Pathology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Masashi Akiya
- Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.,Department of Pathology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Junko Kunieda
- Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.,Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Takeshi Yuasa
- Department of Urology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Shinya Yamamoto
- Department of Urology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Junji Yonese
- Department of Urology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Kengo Takeuchi
- Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.,Department of Pathology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan.,Pathology Project for Molecular Targets, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Kentaro Inamura
- Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan. .,Department of Pathology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan.
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Rasic P, Jovanovic-Tucovic M, Jeremic M, Djuricic SM, Vasiljevic ZV, Milickovic M, Savic D. B7 homologue 3 as a prognostic biomarker and potential therapeutic target in gastrointestinal tumors. World J Gastrointest Oncol 2021; 13:799-821. [PMID: 34457187 PMCID: PMC8371522 DOI: 10.4251/wjgo.v13.i8.799] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Revised: 04/19/2021] [Accepted: 07/07/2021] [Indexed: 02/06/2023] Open
Abstract
The most common digestive system (DS) cancers, including tumors of the gastrointestinal tract (GIT) such as colorectal cancer (CRC), gastric cancer (GC) and esophageal cancer (EC) as well as tumors of DS accessory organs such as pancreatic and liver cancer, are responsible for more than one-third of all cancer-related deaths worldwide, despite the progress that has been achieved in anticancer therapy. Due to these limitations in treatment strategies, oncological research has taken outstanding steps towards a better understanding of cancer cell biological complexity and heterogeneity. These studies led to new molecular target-driven therapeutic approaches. Different in vivo and in vitro studies have revealed significant expression of B7 homologue 3 (B7-H3) among the most common cancers of the GIT, including CRC, GC, and EC, whereas B7-H3 expression in normal healthy tissue of these organs was shown to be absent or minimal. This molecule is able to influence the biological behavior of GIT tumors through the various immunological and nonimmunological molecular mechanisms, and some of them are shown to be the result of B7-H3-related induction of signal transduction pathways, such as Janus kinase 2/signal transducer and activator of transcription 3, phosphatidylinositol 3-kinase/protein kinase B, extracellular signal-regulated kinase, and nuclear factor-κB. B7-H3 exerts an important role in progression, metastasis and resistance to anticancer therapy in these tumors. In addition, the results of many studies suggest that B7-H3 stimulates immune evasion in GIT tumors by suppressing antitumor immune response. Accordingly, it was observed that experimental depletion or inhibition of B7-H3 in gastrointestinal cancers improved antitumor immune response, impaired tumor progression, invasion, angiogenesis, and metastasis and decreased resistance to anticancer therapy. Finally, the high expression of B7-H3 in most common cancers of the GIT was shown to be associated with poor prognosis. In this review, we summarize the established data from different GIT cancer-related studies and suggest that the B7-H3 molecule could be a promising prognostic biomarker and therapeutic target for anticancer immunotherapy in these tumors.
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Affiliation(s)
- Petar Rasic
- Department of Abdominal Surgery, Mother and Child Health Care Institute of Serbia “Dr. Vukan Cupic“, Belgrade 11 000, Serbia
| | - Maja Jovanovic-Tucovic
- Institute of Medical and Clinical Biochemistry, School of Medicine, University of Belgrade, Belgrade 11 000, Serbia
| | - Marija Jeremic
- Institute of Medical and Clinical Biochemistry, School of Medicine, University of Belgrade, Belgrade 11 000, Serbia
| | - Slavisa M Djuricic
- Department of Clinical Pathology, Mother and Child Health Care Institute of Serbia “Dr. Vukan Cupic“, Belgrade 11 000, Serbia
- Faculty of Medicine, University of Banja Luka, Banja Luka 78 000, Bosnia and Herzegovina
| | - Zorica V Vasiljevic
- Department of Clinical Microbiology, Mother and Child Health Care Institute of Serbia “Dr. Vukan Cupic“, Belgrade 11 000, Serbia
| | - Maja Milickovic
- Department of Abdominal Surgery, Mother and Child Health Care Institute of Serbia “Dr. Vukan Cupic“, Belgrade 11 000, Serbia
- School of Medicine, University of Belgrade, Belgrade 11 000, Serbia
| | - Djordje Savic
- Department of Abdominal Surgery, Mother and Child Health Care Institute of Serbia “Dr. Vukan Cupic“, Belgrade 11 000, Serbia
- School of Medicine, University of Belgrade, Belgrade 11 000, Serbia
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Prognostic Implications of Immune-Related Gene Pairs Signatures in Bladder Cancer. JOURNAL OF ONCOLOGY 2021; 2021:5345181. [PMID: 34354750 PMCID: PMC8331311 DOI: 10.1155/2021/5345181] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Accepted: 07/12/2021] [Indexed: 01/01/2023]
Abstract
Compelling evidence indicates that immune function is correlated with the prognosis of bladder cancer (BC). Here, we aimed to develop a clinically translatable immune-related gene pairs (IRGPs) prognostic signature to estimate the overall survival (OS) of bladder cancer. From the 251 prognostic-related IRGPs, 37 prognostic-related IRGPs were identified using LASSO regression. We identified IRGPs with the potential to be prognostic markers. The established risk scores divided BC patients into high and low risk score groups, and the survival analysis showed that risk score was related to OS in the TCGA-training set (p < 0.001; HR = 7.5 [5.3, 10]). ROC curve analysis showed that the AUC for the 1-year, 3-year, and 5-year follow-up was 0.820, 0.883, and 0.879, respectively. The model was verified in the TCGA-testing set and external dataset GSE13507. Multivariate analysis showed that risk score was an independent prognostic predictor in patients with BC. In addition, significant differences were found in gene mutations, copy number variations, and gene expression levels in patients with BC between the high and low risk score groups. Gene set enrichment analysis showed that, in the high-risk score group, multiple immune-related pathways were inhibited, and multiple mesenchymal phenotype-related pathways were activated. Immune infiltration analysis revealed that immune cells associated with poor prognosis of BC were upregulated in the high-risk score group, whereas immune cells associated with a better prognosis of BC were downregulated in the high-risk score group. Other immunoregulatory genes were also differentially expressed between high and low risk score groups. A 37 IRGPs-based risk score signature is presented in this study. This signature can efficiently classify BC patients into high and low risk score groups. This signature can be exploited to select high-risk BC patients for more targeted treatment.
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CD276 is an important player in macrophage recruitment into the tumor and an upstream regulator for PAI-1. Sci Rep 2021; 11:14849. [PMID: 34290311 PMCID: PMC8295264 DOI: 10.1038/s41598-021-94360-9] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Accepted: 07/07/2021] [Indexed: 12/16/2022] Open
Abstract
More than 70% of colorectal, prostate, ovarian, pancreatic and breast cancer specimens show expression of CD276 (B7–H3), a potential immune checkpoint family member. Several studies have shown that high CD276 expression in cancer cells correlates with a poor clinical prognosis. This has been associated with the presence of lower tumor infiltrating leukocytes. Among those, tumor-associated macrophages can comprise up to 50% of the tumor mass and are thought to support tumor growth through various mechanisms. However, a lack of information on CD276 function and interaction partner(s) impedes rigorous evaluation of CD276 as a therapeutic target in oncology. Therefore, we aimed to understand the relevance of CD276 in tumor-macrophage interaction by employing a 3D spheroid coculture system with human cells. Our data show a role for tumor-expressed CD276 on the macrophage recruitment into the tumor spheroid, and also in regulation of the extracellular matrix modulator PAI-1. Furthermore, our experiments focusing on macrophage-expressed CD276 suggest that the antibody-dependent CD276 engagement triggers predominantly inhibitory signaling networks in human macrophages.
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Aberrant expression of WDR4 affects the clinical significance of cancer immunity in pan-cancer. Aging (Albany NY) 2021; 13:18360-18375. [PMID: 34282052 PMCID: PMC8351698 DOI: 10.18632/aging.203284] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Accepted: 06/22/2021] [Indexed: 12/24/2022]
Abstract
Recent publications have presented research showing that WD repeat domain 4 (WDR4) plays a significant role in various kinds of malignant tumours. However, the expression profile of WDR4 is still unspecified, as is its significance in the analysis of human pan-cancer. We conducted an in-depth analysis of three aspects of WDR4 expression patterns from 33 types of cancer and determined the value of WDR4 for prognostic prediction and carcinoma drug resistance prediction. WDR4 was expressed in different cancer cell lines at inconsistent levels. Aberrant expression of WDR4 has been observed in various malignant cancers and is significantly implicated in overall survival outcomes. The expression level of WDR4 is also strongly associated with tumour immunity, such as immune scores and tumour-infiltrating immune cells. The level of WDR4 is related to microsatellite instability and tumour mutation burden in several types of malignancy, and validation studies implied that WDR4-associated terms and pathways are involved in malignancy. We explored the expression level of WDR4 across 33 types of cancer and showed that WDR4 plays a significant role during cancer development. More crucially, WDR4 is associated with immune infiltration, which suggests that WDR4 could be an immunotherapy target in cancers. In summary, our research showed that WDR4 plays a vital role in tumorigenesis and has the potential for to be targeted with treatments.
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Chen Z, Wu T, Yan Z, Zhang M. Identification and Validation of an 11-Ferroptosis Related Gene Signature and Its Correlation With Immune Checkpoint Molecules in Glioma. Front Cell Dev Biol 2021; 9:652599. [PMID: 34249910 PMCID: PMC8262596 DOI: 10.3389/fcell.2021.652599] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 05/13/2021] [Indexed: 12/17/2022] Open
Abstract
Background Glioma is the most common primary malignant brain tumor with significant mortality and morbidity. Ferroptosis, a novel form of programmed cell death (PCD), is critically involved in tumorigenesis, progression and metastatic processes. Methods We revealed the relationship between ferroptosis-related genes and glioma by analyzing the mRNA expression profiles from The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), GSE16011, and the Repository of Molecular Brain Neoplasia Data (REMBRANDT) datasets. The least absolute shrinkage and selection operator (LASSO) Cox regression analysis was performed to construct a ferroptosis-associated gene signature in the TCGA cohort. Glioma patients from the CGGA, GSE16011, and REMBRANDT cohorts were used to validate the efficacy of the signature. Receiver operating characteristic (ROC) curve analysis was applied to measure the predictive performance of the risk score for overall survival (OS). Univariate and multivariate Cox regression analyses of the 11-gene signature were performed to determine whether the ability of the prognostic signature in predicting OS was independent. Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were conducted to identify the potential biological functions and pathways of the signature. Subsequently, we performed single sample gene set enrichment analysis (ssGSEA) to explore the correlation between risk scores and immune status. Finally, seven putative small molecule drugs were predicted by Connectivity Map. Results The 11-gene signature was identified to divide patients into two risk groups. ROC curve analysis indicated the 11-gene signature as a potential diagnostic factor in glioma patients. Multivariate Cox regression analyses showed that the risk score was an independent predictive factor for overall survival. Functional analysis revealed that genes were enriched in iron-related molecular functions and immune-related biological processes. The results of ssGSEA indicated that the 11-gene signature was correlated with the initiation and progression of glioma. The small molecule drugs we selected showed significant potential to be used as putative drugs. Conclusion we identified a novel ferroptosis-related gene signature for prognostic prediction in glioma patients and revealed the relationship between ferroptosis-related genes and immune checkpoint molecules.
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Affiliation(s)
- Zhuohui Chen
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China
| | - Tong Wu
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China
| | - Zhouyi Yan
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China
| | - Mengqi Zhang
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China
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Luo C, Xin H, Yin D, Zhao T, Hu Z, Zhou Z, Sun R, Yao N, Sun Q, Fan J, Huang X, Zhou J, Zhou S. Characterization of immune infiltration in sarcomatoid hepatocellular carcinoma. Aging (Albany NY) 2021; 13:15126-15138. [PMID: 34081621 PMCID: PMC8221324 DOI: 10.18632/aging.203076] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Accepted: 04/29/2021] [Indexed: 12/11/2022]
Abstract
Sarcomatoid hepatocellular carcinoma (sHCC) is a rare type of liver malignancy. Currently, the tumor immune features of sHCC are poorly understood. We recruited 31 patients with resected sHCC for whom tissue samples and complete clinicopathologic and follow-up data were available. To understand the immune infiltration of sHCC, immunohistochemical staining was performed on the resected sHCC samples to compare the expressions of programmed death-1 (PD-1), programmed death-ligand 1 (PD-L1), B7-H3, indoleamine 2,3-dioxygenase (IDO), lymphocyte-activation gene 3 (LAG-3), CD8, FOXP3, and CD68 in tumor and peritumoral tissues. Kaplan-Meier and Cox regression analyses were used to assess the predictive value of immune markers. Sarcomatoid components were characterized with significantly higher expression of PD-L1 and B7-H3 in tumor cells than in conventional HCC components, as well as in peritumoral tissue. Additionally, sarcomatoid components had a higher density of FOXP3+ and LAG-3+ cells and a lower density of CD8+ cells than conventional HCC components or peritumoral tissue. Higher expression of PD-L1 in tumor cells significantly correlated with higher densities of CD8+, PD-1+, and LAG-3+ cells. Increased tumor PD-L1 expression and decreased CD8+ T-cell density were associated with poor overall survival (OS) and disease-free survival (DFS) in patients of sHCC. These findings suggest further characterization on relative mechanism of sHCC immune infiltration may identify therapeutic targets for immunotherapy.
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Affiliation(s)
- Chubin Luo
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China.,Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Shanghai 200032, China
| | - Haoyang Xin
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China.,Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Shanghai 200032, China
| | - Dan Yin
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China.,Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Shanghai 200032, China
| | - Tongyi Zhao
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China.,Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Shanghai 200032, China
| | - Zhiqiang Hu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China.,Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Shanghai 200032, China
| | - Zhengjun Zhou
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China.,Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Shanghai 200032, China
| | - Rongqi Sun
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China.,Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Shanghai 200032, China
| | - Na Yao
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China.,Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Shanghai 200032, China
| | - Qiman Sun
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China.,Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Shanghai 200032, China
| | - Jia Fan
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China.,Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Shanghai 200032, China
| | - Xiaowu Huang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China.,Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Shanghai 200032, China
| | - Jian Zhou
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China.,Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Shanghai 200032, China
| | - Shaolai Zhou
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China.,Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Shanghai 200032, China
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Abou Khouzam R, Rao SP, Venkatesh GH, Zeinelabdin NA, Buart S, Meylan M, Nimmakayalu M, Terry S, Chouaib S. An Eight-Gene Hypoxia Signature Predicts Survival in Pancreatic Cancer and Is Associated With an Immunosuppressed Tumor Microenvironment. Front Immunol 2021; 12:680435. [PMID: 34093582 PMCID: PMC8173254 DOI: 10.3389/fimmu.2021.680435] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Accepted: 05/04/2021] [Indexed: 12/18/2022] Open
Abstract
Intratumoral hypoxia is a widely established element of the pancreatic tumor microenvironment (TME) promoting immune escape, tumor invasion, and progression, while contributing to treatment resistance and poor survival. Despite this critical role, hypoxia is underrepresented in molecular signatures of pancreatic ductal adenocarcinoma (PDA) and concurrent investigations into the hypoxia-immune status are lacking. In this work a literature-based approach was applied to derive an eight-gene hypoxia signature that was validated in fourteen cancer cell lines and in a cohort of PDA. The eight-gene hypoxia signature was significantly associated with overall survival in two distinct PDA datasets and showed independent prognostic value in multivariate analysis. Comparative analysis of tumors according to their hypoxia score (high versus low) determined that tumors with high hypoxia were significantly less enriched in cytotoxic T-cells, and cytolytic activity. In addition, they had lower expression of cytokines and tumor inflammatory markers, pointing to the signature’s ability to discern an immune “cold”, hypoxic TME. Combining the signature with an immune metric highlighted a worse survival probability in patients with high hypoxia and low immune reactivity, indicating that this approach could further refine survival estimates. Hypoxia as determined by our signature, was significantly associated with certain immune checkpoint inhibitors (ICI) biomarkers, suggesting that the signature reflects an aspect of the TME that is worth pursuing in future clinical trials. This is the first work of its kind in PDA, and our findings on the hypoxia-immune tumor contexture are not only relevant for ICI but could also guide combinatorial hypoxia-mediated therapeutic strategies in this cancer type.
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Affiliation(s)
- Raefa Abou Khouzam
- Thumbay Research Institute for Precision Medicine, Gulf Medical University, Ajman, United Arab Emirates
| | - Shyama Prasad Rao
- Bioinformatics Division, Yenepoya Research Center, Yenepoya University, Mangalore, India
| | - Goutham Hassan Venkatesh
- Thumbay Research Institute for Precision Medicine, Gulf Medical University, Ajman, United Arab Emirates
| | - Nagwa Ahmed Zeinelabdin
- Thumbay Research Institute for Precision Medicine, Gulf Medical University, Ajman, United Arab Emirates
| | - Stephanie Buart
- INSERM UMR 1186, Integrative Tumor Immunology and Cancer Immunotherapy, Gustave Roussy, EPHE, Faculty De médecine Univ. Paris-Sud, University Paris-Saclay, Villejuif, France
| | - Maxime Meylan
- Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, F-75006, Paris, France
| | - Manjunath Nimmakayalu
- Graduate Program in Diagnostic Genetics and Genomics, School of Health Professions, MD Anderson Cancer Center, The University of Texas, Houston, TX, United States
| | - Stéphane Terry
- INSERM UMR 1186, Integrative Tumor Immunology and Cancer Immunotherapy, Gustave Roussy, EPHE, Faculty De médecine Univ. Paris-Sud, University Paris-Saclay, Villejuif, France
| | - Salem Chouaib
- Thumbay Research Institute for Precision Medicine, Gulf Medical University, Ajman, United Arab Emirates.,INSERM UMR 1186, Integrative Tumor Immunology and Cancer Immunotherapy, Gustave Roussy, EPHE, Faculty De médecine Univ. Paris-Sud, University Paris-Saclay, Villejuif, France
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38
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Advances in immunotherapeutic targets for childhood cancers: A focus on glypican-2 and B7-H3. Pharmacol Ther 2021; 223:107892. [PMID: 33992682 DOI: 10.1016/j.pharmthera.2021.107892] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 05/05/2021] [Accepted: 05/10/2021] [Indexed: 12/16/2022]
Abstract
Cancer immunotherapies have revolutionized how we can treat adult malignancies and are being translated to pediatric oncology. Chimeric antigen receptor T-cell therapy and bispecific antibodies targeting CD19 have shown success for the treatment of pediatric patients with B-cell acute lymphoblastic leukemia. Anti-GD2 monoclonal antibody has demonstrated efficacy in neuroblastoma. In this review, we summarize the immunotherapeutic agents that have been approved for treating childhood cancers and provide an updated review of molecules expressed by pediatric cancers that are under study or are emerging candidates for future immunotherapies. Advances in our knowledge of tumor immunology and in genome profiling of cancers has led to the identification of new tumor-specific/associated antigens. While cell surface antigens are normally targeted in a major histocompatibility complex (MHC)-independent manner using antibody-based therapies, intracellular antigens are normally targeted with MHC-dependent T cell therapies. Glypican 2 (GPC2) and B7-H3 (CD276) are two cell surface antigens that are expressed by a variety of pediatric tumors such as neuroblastoma and potentially can have a positive impact on the treatment of pediatric cancers in the clinic.
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Michelakos T, Kontos F, Barakat O, Maggs L, Schwab JH, Ferrone CR, Ferrone S. B7-H3 targeted antibody-based immunotherapy of malignant diseases. Expert Opin Biol Ther 2021; 21:587-602. [PMID: 33301369 PMCID: PMC8087627 DOI: 10.1080/14712598.2021.1862791] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Accepted: 12/08/2020] [Indexed: 02/07/2023]
Abstract
Introduction: Recent advances in immuno-oncology and bioengineering have rekindled the interest in monoclonal antibody (mAb)-based immunotherapies for malignancies. Crucial for their success is the identification of tumor antigens (TAs) that can serve as targets. B7-H3, a member of the B7 ligand family, represents such a TA. Although its exact functions and receptor(s) remain unclear, B7-H3 has predominantly a pro-tumorigenic effect mainly by suppressing the anti-tumor functions of T-cells.Areas covered: Initially we present a historical perspective on TA-specific antibodies for diagnosis and treatment of malignancies. Following a description of the TA requirements to be an attractive antibody-based immunotherapy target, we show that B7-H3 fulfills these criteria. We discuss its structure and functions. In a review and pooled analysis, we describe the limited B7-H3 expression in normal tissues and estimate B7-H3 expression frequency in tumors, tumor-associated vasculature and cancer initiating cells (CICs). Lastly, we discuss the association of B7-H3 expression in tumors with poor prognosis.Expert opinion: B7-H3 is an attractive target for mAb-based cancer immunotherapy. B7-H3-targeting strategies are expected to be highly effective and - importantly - safe. To fully exploit the diagnostic and therapeutic potential of B7-H3, its expression in pre-malignant lesions, serum, metastases, and CICs requires further investigation.
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Affiliation(s)
- Theodoros Michelakos
- Department of Surgery, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA
| | - Filippos Kontos
- Department of Surgery, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA
| | - Omar Barakat
- Department of Surgery, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA
| | - Luke Maggs
- Department of Surgery, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA
| | - Joseph H Schwab
- Department of Orthopaedic Surgery, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA
| | - Cristina R Ferrone
- Department of Surgery, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA
| | - Soldano Ferrone
- Department of Surgery, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA
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40
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Geerdes EE, Sideras K, Aziz MH, van Eijck CH, Bruno MJ, Sprengers D, Boor PPC, Kwekkeboom J. Cancer Cell B7-H3 Expression Is More Prevalent in the Pancreato-Biliary Subtype of Ampullary Cancer Than in Pancreatic Cancer. Front Oncol 2021; 11:615691. [PMID: 33996541 PMCID: PMC8117087 DOI: 10.3389/fonc.2021.615691] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Accepted: 03/30/2021] [Indexed: 11/29/2022] Open
Abstract
B7-H3 is an immunomodulatory member of the B7-superfamily with limited expression in normal tissues, but overexpression in several types of cancer. Therefore it is currently being explored as a potential target for cancer immunotherapy. The biological relevance of B7-H3 expression in pancreatic cancer is unclear, while there are no data on B7-H3 expression in ampullary cancer. We aimed to compare intra-tumoral B7-H3 expression between these two closely related cancer types and analyze its association with post-surgical disease course. B7-H3 expression levels were determined by immunohistochemistry in tissue microarrays of resected tumors of 137 pancreatic cancer patients and 83 patients with ampullary cancer of the pancreato-biliary subtype. B7-H3 was more frequently expressed in cancer cells of ampullary cancer patients compared to pancreatic cancer patients (51% versus 21%; p< 0.001). In ampullary cancer patients, but not in pancreatic cancer patients, B7-H3 cancer cell expression was associated with longer disease-free survival and patient survival. However, the prognostic value of B7-H3 was lost upon adjustment for CA19-9 levels. The frequencies of B7-H3 expression in tumor stroma did not differ between the two types of cancer (66% versus 63%). In both cancer types, stromal B7-H3 expression was not associated with post-surgical disease course. Compared to pancreatic cancer, B7-H3 is more frequently expressed in cancer cells of patients with the pancreato-biliary subtype of ampullary cancer. These data suggest that B7-H3 may represent an interesting potential target for immunotherapy in ampullary cancer rather than in pancreatic cancer.
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Affiliation(s)
- Emma E Geerdes
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, Netherlands
| | - Kostandinos Sideras
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, Netherlands.,Department of Surgery, Erasmus MC-University Medical Center, Rotterdam, Netherlands
| | - M Hosein Aziz
- Department of Surgery, Erasmus MC-University Medical Center, Rotterdam, Netherlands
| | - Casper H van Eijck
- Department of Surgery, Erasmus MC-University Medical Center, Rotterdam, Netherlands
| | - Marco J Bruno
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, Netherlands
| | - Dave Sprengers
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, Netherlands
| | - Patrick P C Boor
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, Netherlands
| | - Jaap Kwekkeboom
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, Netherlands
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41
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Liu Z, Zhang D, Liu C, Li G, Chen H, Ling H, Zhang F, Huang D, Wang X, Liu Y, Zhang X. Comprehensive Analysis of Myeloid Signature Genes in Head and Neck Squamous Cell Carcinoma to Predict the Prognosis and Immune Infiltration. Front Immunol 2021; 12:659184. [PMID: 33995379 PMCID: PMC8116959 DOI: 10.3389/fimmu.2021.659184] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Accepted: 04/08/2021] [Indexed: 12/24/2022] Open
Abstract
Myeloid cells are a major heterogeneous cell population in the tumor immune microenvironment (TIME). Imbalance of myeloid response remains a major obstacle to a favorable prognosis and successful immune therapy. Therefore, we aimed to construct a risk model to evaluate the myeloid contexture, which may facilitate the prediction of prognosis and immune infiltration in patients with head and neck squamous cell carcinoma (HNSCC). In our study, six myeloid signature genes (including CCL13, CCR7, CD276, IL1B, LYVE1 and VEGFC) analyzed from 52 differentially expressed myeloid signature genes were finally pooled to establish a prognostic risk model, termed as myeloid gene score (MGS) in a training cohort and validated in a test cohort and an independent external cohort. Furthermore, based on the MGS subgroups, we were able to effectively identify patients with a poor prognosis, aggressive clinical parameters, immune cell infiltration status and immunotherapy response. Thus, MGS may serve as an effective prognostic signature and predictive indicator for immunotherapy response in patients with HNSCC.
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Affiliation(s)
- Zhifeng Liu
- Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, China.,Otolaryngology Major Disease Research Key Laboratory of Hunan Province, Changsha, China.,Clinical Research Center for Pharyngolaryngeal Diseases and Voice Disorders in Hunan Province, Xiangya Hospital, Changsha, China.,Department of Otorhinolaryngology, The First Affiliated Hospital of University of South China, Hengyang, China
| | - Diekuo Zhang
- Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, China.,Otolaryngology Major Disease Research Key Laboratory of Hunan Province, Changsha, China.,Clinical Research Center for Pharyngolaryngeal Diseases and Voice Disorders in Hunan Province, Xiangya Hospital, Changsha, China
| | - Chao Liu
- Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, China.,Otolaryngology Major Disease Research Key Laboratory of Hunan Province, Changsha, China.,Clinical Research Center for Pharyngolaryngeal Diseases and Voice Disorders in Hunan Province, Xiangya Hospital, Changsha, China
| | - Guo Li
- Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, China.,Otolaryngology Major Disease Research Key Laboratory of Hunan Province, Changsha, China.,Clinical Research Center for Pharyngolaryngeal Diseases and Voice Disorders in Hunan Province, Xiangya Hospital, Changsha, China
| | - Huihong Chen
- Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, China.,Otolaryngology Major Disease Research Key Laboratory of Hunan Province, Changsha, China.,Clinical Research Center for Pharyngolaryngeal Diseases and Voice Disorders in Hunan Province, Xiangya Hospital, Changsha, China
| | - Hang Ling
- Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, China.,Otolaryngology Major Disease Research Key Laboratory of Hunan Province, Changsha, China.,Clinical Research Center for Pharyngolaryngeal Diseases and Voice Disorders in Hunan Province, Xiangya Hospital, Changsha, China
| | - Fengyu Zhang
- Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, China.,Otolaryngology Major Disease Research Key Laboratory of Hunan Province, Changsha, China.,Clinical Research Center for Pharyngolaryngeal Diseases and Voice Disorders in Hunan Province, Xiangya Hospital, Changsha, China
| | - Donghai Huang
- Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, China.,Otolaryngology Major Disease Research Key Laboratory of Hunan Province, Changsha, China.,Clinical Research Center for Pharyngolaryngeal Diseases and Voice Disorders in Hunan Province, Xiangya Hospital, Changsha, China
| | - Xingwei Wang
- Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, China.,Otolaryngology Major Disease Research Key Laboratory of Hunan Province, Changsha, China.,Clinical Research Center for Pharyngolaryngeal Diseases and Voice Disorders in Hunan Province, Xiangya Hospital, Changsha, China
| | - Yong Liu
- Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, China.,Otolaryngology Major Disease Research Key Laboratory of Hunan Province, Changsha, China.,Clinical Research Center for Pharyngolaryngeal Diseases and Voice Disorders in Hunan Province, Xiangya Hospital, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, China
| | - Xin Zhang
- Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, China.,Otolaryngology Major Disease Research Key Laboratory of Hunan Province, Changsha, China.,Clinical Research Center for Pharyngolaryngeal Diseases and Voice Disorders in Hunan Province, Xiangya Hospital, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, China
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42
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Lee M, Lu ZH, Shoemaker CB, Tremblay JM, St Croix B, Seaman S, Gonzalez-Pastor R, Kashentseva EA, Dmitriev IP, Curiel DT. Advanced genetic engineering to achieve in vivo targeting of adenovirus utilizing camelid single domain antibody. J Control Release 2021; 334:106-113. [PMID: 33872627 DOI: 10.1016/j.jconrel.2021.04.009] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 04/11/2021] [Indexed: 11/27/2022]
Abstract
For the developing field of gene therapy the successful address of the basic requirement effective gene delivery has remained a critical barrier. In this regard, the "Holy Grail" vector envisioned by the field's pioneers embodied the ability to achieve efficient and specific in vivo gene delivery. Functional linkage of antibody selectivity with viral vector efficiency represented a logical strategy but has been elusive. Here we have addressed this key issue by developing the technical means to pair antibody-based targeting with adenoviral-mediated gene transfer. Our novel method allows efficient and specific gene delivery. Importantly, our studies validated the achievement of this key vectorology mandate in the context of in vivo gene delivery. Vectors capable of effective in vivo delivery embody the potential to dramatically expand the range of successful gene therapy cures.
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Affiliation(s)
- Myungeun Lee
- Division of Cancer Biology, Department of Radiation Oncology, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA
| | - Zhi Hong Lu
- Division of Cancer Biology, Department of Radiation Oncology, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA
| | - Charles B Shoemaker
- Department of Infectious Disease and Global Health, Cummings School of Veterinary Medicine, Tufts University, North Grafton, MA 01536, USA
| | - Jacqueline M Tremblay
- Department of Infectious Disease and Global Health, Cummings School of Veterinary Medicine, Tufts University, North Grafton, MA 01536, USA
| | - Bradley St Croix
- Tumor Angiogenesis Unit, Mouse Cancer Genetics Program (MCGP), National Cancer Institute (NCI), NIH, Frederick, MD 21702, USA
| | - Steven Seaman
- Tumor Angiogenesis Unit, Mouse Cancer Genetics Program (MCGP), National Cancer Institute (NCI), NIH, Frederick, MD 21702, USA
| | - Rebeca Gonzalez-Pastor
- Division of Cancer Biology, Department of Radiation Oncology, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA
| | - Elena A Kashentseva
- Division of Cancer Biology, Department of Radiation Oncology, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA
| | - Igor P Dmitriev
- Division of Cancer Biology, Department of Radiation Oncology, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA
| | - David T Curiel
- Division of Cancer Biology, Department of Radiation Oncology, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA; Biologic Therapeutics Center, Department of Radiation Oncology, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA.
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43
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The complexity of tumour angiogenesis based on recently described molecules. Contemp Oncol (Pozn) 2021; 25:33-44. [PMID: 33911980 PMCID: PMC8063899 DOI: 10.5114/wo.2021.105075] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Accepted: 11/23/2020] [Indexed: 12/13/2022] Open
Abstract
Tumour angiogenesis is a crucial factor associated with tumour growth, progression, and metastasis. The whole process is the result of an interaction between a wide range of different molecules, influencing each other. Herein we summarize novel discoveries related to the less known angiogenic molecules such as galectins, pentraxin-3, Ral-interacting protein of 76 kDa (RLIP76), long non-coding RNAs (lncRNAs), B7-H3, and delta-like ligand-4 (DLL-4) and their role in the process of tumour angiogenesis. These molecules influence the most important molecular pathways involved in the formation of blood vessels in cancer, including the vascular endothelial growth factor (VEGF)-vascular endothelial growth factor receptor interaction (VEGFR), HIF1-a activation, or PI3K/Akt/mTOR and JAK-STAT signalling pathways. Increased expression of galectins, RLIP76, and B7H3 has been proven in several malignancies. Pentraxin-3, which appears to inhibit tumour angiogenesis, shows reduced expression in tumour tissues. Anti-angiogenic treatment based mainly on VEGF inhibition has proved to be of limited effectiveness, leading to the development of drug resistance. The newly discovered molecules are of great interest as a potential source of new anti-cancer therapies. Their role as targets for new drugs and as prognostic markers in neoplasms is discussed in this review.
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44
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Zhang L, Zhang B, Dou Z, Wu J, Iranmanesh Y, Jiang B, Sun C, Zhang J. Immune Checkpoint-Associated Locations of Diffuse Gliomas Comparing Pediatric With Adult Patients Based on Voxel-Wise Analysis. Front Immunol 2021; 12:582594. [PMID: 33815356 PMCID: PMC8010651 DOI: 10.3389/fimmu.2021.582594] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2020] [Accepted: 02/23/2021] [Indexed: 01/22/2023] Open
Abstract
Objective: Pediatric diffuse gliomas (pDGs) are relatively rare and molecularly distinct from pediatric pilocytic astrocytoma and adult DGs. Immunotherapy is a promising therapeutic strategy, requiring a deep understanding of tumor immune profiles. The spatial locations of brain tumors might be related to the molecular profiles. We aimed to analyze the relationship between the immune checkpoint molecules with the locations of DGs comparing pediatric with adult patients. Method: We studied 20 pDGs patients (age ≤ 21 years old), and 20 paired adult patients according to gender and histological types selected from 641 adult patients with DGs. Immune checkpoint molecules including B7-H3, CD47, and PD-L1, as well as tumor-infiltrating lymphocytes (TILs) and tumor-associated macrophages (TAMs), were manifested by immunohistochemical staining. Expression difference analyses and Spearman's correlation were performed. MRI data were voxel-wise normalized, segmented, and analyzed by Fisher's exact test to construct the tumor frequency and p value heatmaps. Survival analyses were conducted by Log-rank tests. Result: The median age of pediatric patients was 16 years. 55% and 30% of patients were WHO II and III grades, respectively. The left frontal lobe and right cerebellum were the statistically significant locations for pDGs, while the anterior horn of ventricles for adult DGs. A potential association between the expression of PD-L1 and TAMs was found in pDGs (p = 0.002, R = 0.670). The right posterior external capsule and the lateral side of the anterior horn of the left ventricle were predominant locations for the adult patients with high expression of B7-H3 and low expression of PD-L1 compared to pediatric ones, respectively. Pediatric patients showed significantly improved overall survival compared with adults. The prognostic roles of immune checkpoint molecules and TILs/TAMs were not significantly different between the two groups. Conclusion: Immune checkpoint-associated locations of diffuse gliomas comparing pediatric with adult patients could be helpful for the immunotherapy decisions and design of clinical trials.
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Affiliation(s)
- Li Zhang
- Department of Oncology, Daqing Oilfield General Hospital, Daqing, China
| | - Buyi Zhang
- Department of Pathology, School of Medicine, The Second Affiliated Hospital of Zhejiang University, Hangzhou, China
| | - Zhangqi Dou
- Department of Neurosurgery, School of Medicine, The Second Affiliated Hospital of Zhejiang University, Hangzhou, China
| | - Jiawei Wu
- Department of Neurosurgery, School of Medicine, The Second Affiliated Hospital of Zhejiang University, Hangzhou, China
| | - Yasaman Iranmanesh
- Department of Neurosurgery, School of Medicine, The Second Affiliated Hospital of Zhejiang University, Hangzhou, China
| | - Biao Jiang
- Department of Radiology, School of Medicine, The Second Affiliated Hospital of Zhejiang University, Hangzhou, China
| | - Chongran Sun
- Department of Neurosurgery, School of Medicine, The Second Affiliated Hospital of Zhejiang University, Hangzhou, China
| | - Jianmin Zhang
- Department of Neurosurgery, School of Medicine, The Second Affiliated Hospital of Zhejiang University, Hangzhou, China
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Zhou L, Jiang Z, Gu J, Gu W, Han S. B7-H3 and digestive system cancers. EUR J INFLAMM 2021. [DOI: 10.1177/20587392211000581] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Digestive system cancers (DSC) are the most common cancers worldwide and often associated with poor prognosis because of their characteristics of invasive and metastatic. Thus, it is particularly necessary to find novel molecular targets for early diagnosis, as well as targeted treatment of DSC. B7-H3, which was previously referred to as a modulatory ligand that regulate T-cell-mediated immune reaction, is a B7-family member of co-stimulatory biomolecules, and in recent years it was found that its concentration was remarkably up modulated in serum, as well as tissues of DSC patients. Numerous studies have documented that B7-H3 has a vital function in the DSC. Herein, we summarize the current literature on diagnosis and prognosis potential of B7-H3 in DSC including those of the esophagus, gastric, liver, pancreas, and colon.
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Affiliation(s)
- Liyun Zhou
- Zhengzhou University People’s Hospital, Zhengzhou
- Henan Provincial People’s Hospital, Zhengzhou
| | - Zhenhua Jiang
- Zhengzhou University People’s Hospital, Zhengzhou
- Henan Provincial People’s Hospital, Zhengzhou
| | - Jing Gu
- Department of Dermatology, Henan Honliv Hospital, Changyuan
| | - Wenhui Gu
- Zhengzhou University People’s Hospital, Zhengzhou
- Henan Provincial People’s Hospital, Zhengzhou
| | - Shuangyin Han
- Zhengzhou University People’s Hospital, Zhengzhou
- Henan Provincial People’s Hospital, Zhengzhou
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Want MY, Tsuji T, Singh PK, Thorne JL, Matsuzaki J, Karasik E, Gillard B, Cortes Gomez E, Koya RC, Lugade A, Odunsi K, Battaglia S. WHSC1/NSD2 regulates immune infiltration in prostate cancer. J Immunother Cancer 2021; 9:jitc-2020-001374. [PMID: 33589522 PMCID: PMC7887377 DOI: 10.1136/jitc-2020-001374] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/20/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Immunotherapy in prostate cancer (PCa) lags behind the progresses obtained in other cancer types partially because of its limited immune infiltration. Tumor-resident immune cells have been detected in the prostate, but the regulatory mechanisms that govern tumor infiltration are still poorly understood. To address this gap, we investigated the role of Wolf-Hirschhorn syndrome candidate 1 (WHSC1), a histone methyltransferase enzyme that targets dimethyl and trimethyl H3K36. WHSC1 is known to promote malignant growth and progression in multiple tumors, but its role in the interface between PCa and immune system is unknown. METHODS RNA Sequencing (RNASeq) data from patients with PCa from The Cancer Genome Atlas (TCGA) were collected and divided into top/bottom 30% based on the expression of WHSC1 and disease-free survival was calculated. Publicly available chromatin immunoprecipitation (ChIPSeq) data were obtained from Cistrome and integrated with the available RNASeq data. RNASeq, ATACSeq and methylomic were analyzed using R Bioconductor packages comparing C42 cells with or without stable knockdown on WHSC1. Flow cytometry was used to measure Major Histocompatibility complex (MHC) levels, MHC-bound ovalbumin and tumor infiltration. C57B6 and NOD scid gamma (NSG) mice were subcutaneously grafted with TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) C2 cells and treated with MCTP39 (10 mg/kg); tumor size was monitored over time and curves were compared using permutation analyses. All analyses used a significance threshold of 0.05. RESULTS Leveraging TCGA data, we demonstrated that elevated WHSC1 levels positively correlate with the presence of an immunosuppressive microenvironment. We validated those results in vitro, demonstrating that genetic and pharmacological inhibition of WHSC1 restores antigen presentation. This occurs via an elegant epigenetic regulation of gene expression at the chromatin and DNA methylation levels. In vivo studies in immunocompetent mice also show an increased frequency of CD8+ T cells in tumors from mice treated with WHSC1 inhibitor, supporting the hypothesis that the antitumor effect following WHSC1 inhibition requires a fully functional immune system. CONCLUSIONS This study demonstrates a novel role for WHSC1 in defining immune infiltration in PCa, with significant future implications for the use of immunotherapies in prostate malignancies.
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Affiliation(s)
- Muzamil Y Want
- Center For Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
| | - Takemasa Tsuji
- Center For Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
| | - Prashant K Singh
- Genomics Shared Resource, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
| | - James L Thorne
- School of Food Science and Nutrition, Faculty of Environment, University of Leeds, Leeds, West Yorkshire, UK
| | - Junko Matsuzaki
- Center For Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
| | - Ellen Karasik
- Department of Pharmacology and Experimental Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
| | - Bryan Gillard
- Department of Pharmacology and Experimental Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
| | - Eduardo Cortes Gomez
- Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
| | - Richard C Koya
- Center For Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
| | - Amit Lugade
- Center For Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
| | - Kunle Odunsi
- Center For Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
| | - Sebastiano Battaglia
- Center For Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
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47
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Lu Z, Zhao ZX, Cheng P, Huang F, Guan X, Zhang MG, Chen HP, Liu Z, Jiang Z, Zheng ZX, Zou SM, Wang XS. B7-H3 immune checkpoint expression is a poor prognostic factor in colorectal carcinoma. Mod Pathol 2020; 33:2330-2340. [PMID: 32514163 DOI: 10.1038/s41379-020-0587-z] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Revised: 05/24/2020] [Accepted: 05/25/2020] [Indexed: 12/24/2022]
Abstract
Although PD-1/PD-L1 immunotherapy has been used successfully in treating many cancers, metastatic colorectal cancer (CRC) patients are not as responsive. B7-H3 is a promising target for immunotherapy and we found it to have the highest expression among B7-CD28 family members in CRC. Thus, the aim of the present study was to investigate B7-H3 expression in a large CRC cohort. B7-H3, B7-H4, and PD-L1 protein levels and differential lymphocyte infiltration were evaluated in tissue microarrays from 805 primary tumors and matched metastases. The relationships between immune markers, patient characteristics, and survival outcomes were determined. B7-H3 (50.9%) was detected in more primary tumors than B7-H4 (29.1%) or PD-L1 (29.2%), and elevated B7-H3 expression was associated with advanced overall stage. Co-expression of B7-H3 only with B7-H4 or PD-L1 was infrequent in primary tumors (6.3%, 5.7%, respectively). Moreover, B7-H3 in primary tumors was positively correlated with their respective expression at metastatic sites (ρ = 0.631; p < 0.001). No significant relationships between B7-H4 and PD-L1 and survival were observed; however, B7-H3 overexpression in primary tumors was significantly related to decreased disease-free survival. A positive relationship between B7-H3 expression and high density CD45RO T cell was observed in primary tumors, whereas B7-H4 and PD-L1 overexpression were related to CD3 T-cell infiltration. In conclusion, compared with B7-H4 and PD-L1, B7-H3 expression exhibited a higher prevalence and was significantly related to aggressiveness, worse prognosis and CD45RO T-cell infiltration in primary tumors. Further exploration of this potential target of immunotherapy in CRC patients is warranted.
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Affiliation(s)
- Zhao Lu
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zhi-Xun Zhao
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Pu Cheng
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Fei Huang
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xu Guan
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ming-Guang Zhang
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hai-Peng Chen
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zheng Liu
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zheng Jiang
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zhao-Xu Zheng
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| | - Shuang-Mei Zou
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| | - Xi-Shan Wang
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
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48
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Flem-Karlsen K, Fodstad Ø, Nunes-Xavier CE. B7-H3 Immune Checkpoint Protein in Human Cancer. Curr Med Chem 2020; 27:4062-4086. [PMID: 31099317 DOI: 10.2174/0929867326666190517115515] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Revised: 04/29/2019] [Accepted: 05/04/2019] [Indexed: 02/07/2023]
Abstract
B7-H3 belongs to the B7 family of immune checkpoint proteins, which are important regulators of the adaptive immune response and emerging key players in human cancer. B7-H3 is a transmembrane protein expressed on the surface of tumor cells, antigen presenting cells, natural killer cells, tumor endothelial cells, but can also be present in intra- and extracellular vesicles. Additionally, B7-H3 may be present as a circulating soluble isoform in serum and other body fluids. B7-H3 is overexpressed in a variety of tumor types, in correlation with poor prognosis. B7-H3 is a promising new immunotherapy target for anti-cancer immune response, as well as a potential biomarker. Besides its immunoregulatory role, B7-H3 has intrinsic pro-tumorigenic activities related to enhanced cell proliferation, migration, invasion, angiogenesis, metastatic capacity and anti-cancer drug resistance. B7-H3 has also been found to regulate key metabolic enzymes, promoting the high glycolytic capacity of cancer cells. B7-H3 receptors are still not identified, and little is known about the molecular mechanisms underlying B7-H3 functions. Here, we review the current knowledge on the involvement of B7-H3 in human cancer.
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Affiliation(s)
- Karine Flem-Karlsen
- Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway.,Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Øystein Fodstad
- Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway.,Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Caroline E Nunes-Xavier
- Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway
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49
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Xu Y, Xiao Y, Luo C, Liu Q, Wei A, Yang Y, Zhao L, Wang Y. Blocking PD-1/PD-L1 by an ADCC enhanced anti-B7-H3/PD-1 fusion protein engages immune activation and cytotoxicity. Int Immunopharmacol 2020; 84:106584. [PMID: 32422527 DOI: 10.1016/j.intimp.2020.106584] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2020] [Revised: 04/28/2020] [Accepted: 05/07/2020] [Indexed: 12/15/2022]
Abstract
Antibody therapy based on PD-1/PD-L1 blocking or ADCC effector has produced significant clinical benefit for cancer patients. We generated a novel anti-B7-H3 antibody (07B) and engineered the Fc fragment to enhance ADCC. To improve efficacy and tumor selectivity, we developed anti-B7-H3/PD-1 bispecific fusion proteins that simultaneously engaged tumor associate marker B7-H3 and immune suppressing ligand PD-L1 as well as enhanced ADCC to promote potent and highly selective tumor killing. Fusion proteins were designed by fusing human PD-1 extra domain to 07B in four different formats and showed good binding capacity to both targets. Indeed, the affinity of fusion proteins to B7-H3 is over 10,000 fold higher compared to that of the analogous PD-L1 and the blocking of fusion proteins to PD-L1 was worse but it greatly enhanced when bound to B7-H3, thus achieving directly PD-L1-blockade to B7-H3-expressing tumor cells. Importantly, IL-2 production was enhanced by fusion proteins from staphylococcal enterotoxin B (SEB) stimulated PBMC. Similarly, cytokines induced by fusion proteins was enhanced when co-cultured with stimulated CD8+ T cells and B7-H3/PD-L1 transfected raji cells. Additionally, fusion proteins improved activation to CD16a by Fc modification and delivered selective cytotoxicity to B7-H3 expressing tumor cells. In conclusion, fusion proteins blocked the PD-1/PD-L1 signal pathway and significantly increased potency of ADCC in a B7-H3-directed manner, thereby selectively activating CD8+ T cells and enhancing natural killing towards tumor. This novel fusion protein with its unique targeting preference may be useful to enhance efficacy and safety of immunotherapy for B7-H3-overexpressing malignancies.
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Affiliation(s)
- Yao Xu
- Sanhome-CPU Joint Laboratory, China Pharmaceutical University, Nanjing 211198, PR China; Sanhome R&D Centre, Nanjing Sanhome Pharmaceutical Co., Ltd., Nanjing 221116, PR China; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
| | - Yang Xiao
- Sanhome R&D Centre, Nanjing Sanhome Pharmaceutical Co., Ltd., Nanjing 221116, PR China
| | - Cheng Luo
- Sanhome R&D Centre, Nanjing Sanhome Pharmaceutical Co., Ltd., Nanjing 221116, PR China
| | - Qingxia Liu
- Sanhome-CPU Joint Laboratory, China Pharmaceutical University, Nanjing 211198, PR China; Sanhome R&D Centre, Nanjing Sanhome Pharmaceutical Co., Ltd., Nanjing 221116, PR China
| | - Aiqi Wei
- Sanhome R&D Centre, Nanjing Sanhome Pharmaceutical Co., Ltd., Nanjing 221116, PR China
| | - Yang Yang
- Sanhome R&D Centre, Nanjing Sanhome Pharmaceutical Co., Ltd., Nanjing 221116, PR China
| | - Liwen Zhao
- Sanhome R&D Centre, Nanjing Sanhome Pharmaceutical Co., Ltd., Nanjing 221116, PR China
| | - Yong Wang
- Sanhome-CPU Joint Laboratory, China Pharmaceutical University, Nanjing 211198, PR China; Sanhome R&D Centre, Nanjing Sanhome Pharmaceutical Co., Ltd., Nanjing 221116, PR China.
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50
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Wierzbinska JA, Toth R, Ishaque N, Rippe K, Mallm JP, Klett LC, Mertens D, Zenz T, Hielscher T, Seifert M, Küppers R, Assenov Y, Lutsik P, Stilgenbauer S, Roessner PM, Seiffert M, Byrd J, Oakes CC, Plass C, Lipka DB. Methylome-based cell-of-origin modeling (Methyl-COOM) identifies aberrant expression of immune regulatory molecules in CLL. Genome Med 2020; 12:29. [PMID: 32188505 PMCID: PMC7081711 DOI: 10.1186/s13073-020-00724-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Accepted: 02/11/2020] [Indexed: 02/07/2023] Open
Abstract
Background In cancer, normal epigenetic patterns are disturbed and contribute to gene expression changes, disease onset, and progression. The cancer epigenome is composed of the epigenetic patterns present in the tumor-initiating cell at the time of transformation, and the tumor-specific epigenetic alterations that are acquired during tumor initiation and progression. The precise dissection of these two components of the tumor epigenome will facilitate a better understanding of the biological mechanisms underlying malignant transformation. Chronic lymphocytic leukemia (CLL) originates from differentiating B cells, which undergo extensive epigenetic programming. This poses the challenge to precisely determine the epigenomic ground state of the cell-of-origin in order to identify CLL-specific epigenetic aberrations. Methods We developed a linear regression model, methylome-based cell-of-origin modeling (Methyl-COOM), to map the cell-of-origin for individual CLL patients based on the continuum of epigenomic changes during normal B cell differentiation. Results Methyl-COOM accurately maps the cell-of-origin of CLL and identifies CLL-specific aberrant DNA methylation events that are not confounded by physiologic epigenetic B cell programming. Furthermore, Methyl-COOM unmasks abnormal action of transcription factors, altered super-enhancer activities, and aberrant transcript expression in CLL. Among the aberrantly regulated transcripts were many genes that have previously been implicated in T cell biology. Flow cytometry analysis of these markers confirmed their aberrant expression on malignant B cells at the protein level. Conclusions Methyl-COOM analysis of CLL identified disease-specific aberrant gene regulation. The aberrantly expressed genes identified in this study might play a role in immune-evasion in CLL and might serve as novel targets for immunotherapy approaches. In summary, we propose a novel framework for in silico modeling of reference DNA methylomes and for the identification of cancer-specific epigenetic changes, a concept that can be broadly applied to other human malignancies. Electronic supplementary material Supplementary information accompanies this paper at 10.1186/s13073-020-00724-7.
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Affiliation(s)
- Justyna A Wierzbinska
- Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.,Faculty of Biosciences, Heidelberg University, Heidelberg, Germany.,The German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Reka Toth
- Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany
| | - Naveed Ishaque
- The German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Karsten Rippe
- The German Cancer Consortium (DKTK), Heidelberg, Germany.,Division of Chromatin Networks, DKFZ, Heidelberg, Germany
| | - Jan-Philipp Mallm
- The German Cancer Consortium (DKTK), Heidelberg, Germany.,Division of Chromatin Networks, DKFZ, Heidelberg, Germany
| | - Lara C Klett
- Faculty of Biosciences, Heidelberg University, Heidelberg, Germany.,Division of Chromatin Networks, DKFZ, Heidelberg, Germany
| | - Daniel Mertens
- The German Cancer Consortium (DKTK), Heidelberg, Germany.,Mechanisms of Leukemogenesis, DKFZ, Heidelberg, Germany
| | - Thorsten Zenz
- Experimental Hematology Lab, University Hospital Zurich, Zurich, Switzerland
| | | | - Marc Seifert
- Group Molecular Genetics, Essen University Hospital, Essen, Germany
| | - Ralf Küppers
- Group Molecular Genetics, Essen University Hospital, Essen, Germany
| | - Yassen Assenov
- Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany
| | - Pavlo Lutsik
- Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany
| | | | | | | | - John Byrd
- Department of Internal Medicine, Division of Hematology, The Ohio State University, Columbus, USA
| | - Christopher C Oakes
- Department of Internal Medicine, Division of Hematology, The Ohio State University, Columbus, USA.,Department of Biomedical Informatics, The Ohio State University, Columbus, USA
| | - Christoph Plass
- Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany. .,The German Cancer Consortium (DKTK), Heidelberg, Germany.
| | - Daniel B Lipka
- The German Cancer Consortium (DKTK), Heidelberg, Germany. .,Section Translational Cancer Epigenomics, Division of Translational Medical Oncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120, Heidelberg, Germany. .,National Center for Tumor Diseases (NCT), Heidelberg, Germany. .,Faculty of Medicine, Medical Center, Otto-von-Guericke-University, 39120, Magdeburg, Germany.
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