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Deng W, Wu L, Chen L, Wang K, Lin N, Zhu L, Chen J. Development of B7-H3 targeted CAR-T cells for renal cell carcinoma therapy: in vitro and in vivo efficacy. Clin Transl Oncol 2025; 27:2667-2678. [PMID: 39560834 DOI: 10.1007/s12094-024-03792-y] [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: 08/21/2024] [Accepted: 11/08/2024] [Indexed: 11/20/2024]
Abstract
PURPOSE This study aims to develop chimeric antigen receptor (CAR)-T cells specifically targeting B7-H3-expressing renal cell carcinoma (RCC) and to evaluate the feasibility of B7-H3 CAR-T therapy for RCC. METHODS We analyzed B7-H3 expression in RCC using bioinformatics approaches and confirmed it in tissues and cell lines through immunohistochemical staining and Western blot analysis. A lentiviral vector containing a B7-H3 specific CAR was constructed and transfected into human T cells, with CAR expression verified by flow cytometry. Cytotoxic efficacy was evaluated in co-culture experiments, measuring the production of interferon-gamma (IFN-γ), interleukin-2 (IL-2), granzyme B, and lactate dehydrogenase (LDH) release. Xenograft models in nude mice were used to evaluate tumor growth inhibition by B7-H3 CAR-T cells. RESULTS B7-H3 was significantly expressed in RCC and associated with poor prognosis. Elevated levels of B7-H3 expression were validated in both RCC tissues and cell lines. A B7-H3-specific CAR-T cell was developed, achieving a CAR transduction efficiency of 39.85%, as assessed by flow cytometry. In vitro co-culture assays demonstrated that the CAR-T cells exhibited substantial cytotoxic activity against RCC cell lines, with this activity positively correlating with the effector-to-target ratio. Furthermore, the secretion levels of IFN-γ, IL-2, granzyme B, and LDH were significantly increased compared to the control groups. In vivo experiments further confirmed that B7-H3 CAR-T cells significantly inhibited tumor growth. CONCLUSION The current study suggests that B7-H3 CAR-T cells exhibit significant efficacy in targeting and eliminating RCC cells, indicating a promising cellular immunotherapy approach for RCC treatment.
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Affiliation(s)
- Wenyi Deng
- Institute of Clinical Medicine, the Second Affiliated Hospital of Hainan Medical University, 368 Yehai Avenue, Haikou, 570311, Hainan, China
| | - Lvying Wu
- Institute of Clinical Medicine, the Second Affiliated Hospital of Hainan Medical University, 368 Yehai Avenue, Haikou, 570311, Hainan, China
| | - Liuyan Chen
- Institute of Clinical Medicine, the Second Affiliated Hospital of Hainan Medical University, 368 Yehai Avenue, Haikou, 570311, Hainan, China
| | - Kuanyin Wang
- Minimally Invasive Urology and Translational Medicine Center, Fuzhou First General Hospital Affiliated With Fujian Medical University, 190th Dadao Road, Fuzhou, 350009, Fujian, China
- Department of Urology, the Second Affiliated Hospital of Hainan Medical University, Haikou, 570311, Hainan, China
| | - Na Lin
- Minimally Invasive Urology and Translational Medicine Center, Fuzhou First General Hospital Affiliated With Fujian Medical University, 190th Dadao Road, Fuzhou, 350009, Fujian, China
| | - Lingfeng Zhu
- Minimally Invasive Urology and Translational Medicine Center, Fuzhou First General Hospital Affiliated With Fujian Medical University, 190th Dadao Road, Fuzhou, 350009, Fujian, China.
- Department of Urology, the Second Affiliated Hospital of Hainan Medical University, Haikou, 570311, Hainan, China.
| | - Jin Chen
- Institute of Clinical Medicine, the Second Affiliated Hospital of Hainan Medical University, 368 Yehai Avenue, Haikou, 570311, Hainan, China.
- Minimally Invasive Urology and Translational Medicine Center, Fuzhou First General Hospital Affiliated With Fujian Medical University, 190th Dadao Road, Fuzhou, 350009, Fujian, 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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Sharafi Monfared M, Nazmi S, Parhizkar F, Jafari D. Soluble B7 and TNF family in colorectal cancer: Serum level, prognostic and treatment value. Hum Immunol 2025; 86:111232. [PMID: 39793378 DOI: 10.1016/j.humimm.2025.111232] [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: 10/24/2024] [Revised: 12/25/2024] [Accepted: 01/02/2025] [Indexed: 01/13/2025]
Abstract
Soluble immune checkpoints (sIC) are crucial factors in the immune system. They regulate immune responses by transforming intercellular signals via binding to their membrane-bound receptor or ligand. Moreover, soluble ICs are vital in immune regulation, cancer development, and prognosis. They can be identified and measured in various tumor microenvironments. Recently, sICs have become increasingly important in clinically assessing malignancies like colorectal cancer (CRC) patients. This review explores the evolving role of the soluble B7 family and soluble tumor necrosis factor (TNF) superfamily members in predicting disease progression, treatment response, and overall patient outcomes in CRC. We comprehensively analyze the diagnostic and prognostic potential of soluble immune checkpoints in CRC. Understanding the role of these soluble immune checkpoints in CRC management and their potential as targets for precision medicine approaches can be critical for improving outcomes for patients with colorectal cancer.
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Affiliation(s)
- Mohanna Sharafi Monfared
- Student's Research Committee, Zanjan University of Medical Sciences, Zanjan, Iran; School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Sina Nazmi
- Student's Research Committee, Zanjan University of Medical Sciences, Zanjan, Iran; School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Forough Parhizkar
- Department of Immunology, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Davood Jafari
- Department of Immunology, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran.
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Azizi M, Mokhtari Z, Tavana S, Bemani P, Heidari Z, Ghazavi R, Rezaei M. A Comprehensive Study on the Prognostic Value and Clinicopathological Significance of Different Immune Checkpoints in Patients With Colorectal Cancer: A Systematic Review and Meta-Analysis. CURRENT THERAPEUTIC RESEARCH 2024; 101:100760. [PMID: 39434898 PMCID: PMC11492099 DOI: 10.1016/j.curtheres.2024.100760] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Accepted: 08/30/2024] [Indexed: 10/23/2024]
Abstract
Background The prognostic significance of immune checkpoint expression in the tumor microenvironment has been widely investigated in colorectal cancers. However, the results of these studies are inconsistent and limited to some immune checkpoints. Objective The study aimed to investigate the correlation between different immune checkpoint expression and clinicopathological features and prognostic parameters. Methods We conducted a systematic review and meta-analysis of the published literature in PubMed, Web of Science-Core Collection, Scopus, Embase, and Cochrane databases to summarize the association between various immune checkpoints expression on both tumor cells and immune cells with clinicopathological features and prognostic parameters in patients with colorectal cancer. Results One hundred four studies incorporating 22,939 patients were included in our meta-analysis. Our results showed that among the B7 family, the high expression of B7H3, B7H4, PD-1, and PD-L1 on tumor cells and tumor tissue was significantly associated with higher T stage, advanced tumor, node, metastasis (TNM) stage, presence of vascular invasion, and lymphatic invasion. In addition, patients with high expression of B7H3, B7H4, PD-1, PD-L1, and PD-L2 were associated with shorter overall survival. High expression of PD-1 and PD-L1 in immune cells correlated with the absence of lymph node metastasis, lower TNM stage, early T stage, poor overall survival, and disease-free survival, respectively. Moreover, we found significant positive correlations between CD70 and Galectin-3 expression with advanced T stage. HLA-II overexpression was correlated with the absence of lymph node metastasis (odds ratio = 0.21, 95% CI = 0.11-0.38, P < 0.001) and early TNM stage (odds ratio = 0.35, 95% CI = 0.26-0.47, P < 0.001). Conclusions Overexpression of B7H3, B7H4, PD-1, PD-L1, PD-L2, CD70, and Galectin-3 on tumors is significantly associated with unfavorable clinicopathological characteristics and poor prognostic factors. Hence, these immune checkpoints can serve as predictive biomarkers for prognosis and the clinicopathological features of colorectal cancer because this is essential to identify patients suitable for anticancer therapy with immune checkpoint inhibitors.
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Affiliation(s)
- Mahdieh Azizi
- Department of Immunology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Zahra Mokhtari
- Department of Immunology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Shirin Tavana
- Department of Immunology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Peyman Bemani
- Department of Immunology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Zahra Heidari
- Department of Biostatistics and Epidemiology, Faculty of Health, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Roghayeh Ghazavi
- Department of Knowledge and Information Science, Faculty of Education and Psychology, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Marzieh Rezaei
- Department of Immunology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
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Curcean S, Hendea RM, Buiga R, Tipcu A, Curcean A, Vlad C, Fekete Z, Muntean AS, Martin D, Irimie A. B7H3 Immune Checkpoint Overexpression Is Associated with Decreased Complete Response Rates to Neoadjuvant Therapy in Locally Advanced Rectal Cancer. Diagnostics (Basel) 2024; 14:2023. [PMID: 39335702 PMCID: PMC11431099 DOI: 10.3390/diagnostics14182023] [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: 08/20/2024] [Revised: 09/04/2024] [Accepted: 09/11/2024] [Indexed: 09/30/2024] Open
Abstract
BACKGROUND AND OBJECTIVES Rectal cancer accounts for approximately one-third of colorectal cancers, with over 340,000 deaths globally in 2022. Despite advancements in treatment, the five-year overall survival for locally advanced rectal cancer (LARC) remains at 74%, with significant morbidity. B7H3 (CD276), an immune checkpoint protein, plays a role in tumor progression and resistance to therapy, and correlates with poor prognosis in various cancers, including colorectal cancer. This study aims to evaluate the expression of B7H3 in LARC and its impact on overall complete response (oCR) rates to neoadjuvant therapy. METHODS A retrospective study was conducted on 60 patients with LARC who received neoadjuvant chemoradiation (nCRT) followed by total mesorectal excision (TME). B7H3 expression was assessed using immunohistochemistry on surgical specimens. Expression levels were categorized as high or low based on a composite score, and their association with oCR rates was analyzed. RESULTS High B7H3 expression was observed in 60% of patients, with 73.5% showing expression in more than 50% of tumor cells. Patients who achieved oCR had significantly lower B7H3 expression compared to those with residual disease (p < 0.001). No nuclear expression of B7H3 was detected. No significant correlation was found between B7H3 expression and other clinicopathological variables, except for a higher likelihood of non-restorative surgery in patients with elevated B7H3 levels (p = 0.049). Mucinous adenocarcinoma had high expression of B7H3. CONCLUSIONS Elevated B7H3 expression is associated with reduced oCR rates in LARC, highlighting its potential role as a prognostic biomarker. Further studies with larger cohorts are warranted to validate these findings and explore B7H3-targeted therapies as a treatment strategy for LARC.
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Affiliation(s)
- Sebastian Curcean
- Department of Radiation Oncology, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
- Department of Radiation Oncology, “Prof. Dr. Ion Chiricuta” Oncology Institute, 400015 Cluj-Napoca, Romania
| | - Raluca Maria Hendea
- Department of Pathology, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
| | - Rares Buiga
- Department of Pathology, “Prof. Dr. Ion Chiricuta” Oncology Institute, 400015 Cluj-Napoca, Romania
| | - Alexandru Tipcu
- Faculty of Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
| | - Andra Curcean
- Department of Imaging, Affidea Center, 400487 Cluj-Napoca, Romania
| | - Catalin Vlad
- Department of Oncological Surgery and Gynecological Oncology, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
- Department of Oncological Surgery, “Prof. Dr. Ion Chiricuta” Oncology Institute, 400015 Cluj-Napoca, Romania
| | - Zsolt Fekete
- Department of Radiation Oncology, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
- Department of Radiation Oncology, “Prof. Dr. Ion Chiricuta” Oncology Institute, 400015 Cluj-Napoca, Romania
| | - Alina-Simona Muntean
- Department of Radiation Oncology, “Prof. Dr. Ion Chiricuta” Oncology Institute, 400015 Cluj-Napoca, Romania
| | - Daniela Martin
- Department of Radiation Oncology, “Prof. Dr. Ion Chiricuta” Oncology Institute, 400015 Cluj-Napoca, Romania
| | - Alexandru Irimie
- Department of Oncological Surgery and Gynecological Oncology, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
- Department of Oncological Surgery, “Prof. Dr. Ion Chiricuta” Oncology Institute, 400015 Cluj-Napoca, Romania
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Yuan L, Wang Y, Shen X, Ma F, Wang J, Yan F. Soluble form of immune checkpoints in autoimmune diseases. J Autoimmun 2024; 147:103278. [PMID: 38943864 DOI: 10.1016/j.jaut.2024.103278] [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: 02/01/2024] [Revised: 05/03/2024] [Accepted: 06/19/2024] [Indexed: 07/01/2024]
Abstract
Immune checkpoints are essential regulators of immune responses, either by activating or suppressing them. Consequently, they are regarded as pivotal elements in the management of infections, cancer, and autoimmune disorders. In recent years, researchers have identified numerous soluble immune checkpoints that are produced through various mechanisms and demonstrated biological activity. These soluble immune checkpoints can be produced and distributed in the bloodstream and various tissues, with their roles in immune response dysregulation and autoimmunity extensively documented. This review aims to provide a thorough overview of the generation of various soluble immune checkpoints, such as sPD-1, sCTLA-4, sTim-3, s4-1BB, sBTLA, sLAG-3, sCD200, and the B7 family, and their importance as indicators for the diagnosis and prediction of autoimmune conditions. Furthermore, the review will investigate the potential pathological mechanisms of soluble immune checkpoints in autoimmune diseases, emphasizing their association with autoimmune diseases development, prognosis, and treatment.
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Affiliation(s)
- Li Yuan
- Geriatric Diseases Institute of Chengdu, Department of Clinical Laboratory, Chengdu Fifth People's Hospital, Chengdu, Sichuan Province, China
| | - Yuxia Wang
- Geriatric Intensive Care Unit, Sichuan Geriatric Medical Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan Province, China
| | - Xuxia Shen
- Geriatric Diseases Institute of Chengdu, Department of Clinical Laboratory, Chengdu Fifth People's Hospital, Chengdu, Sichuan Province, China
| | - Fujun Ma
- Department of Training, Chengdu Fifth People's Hospital, Chengdu, Sichuan Province, China
| | - Jun Wang
- Department of Respiratory and Critical Care Medicine, Chengdu Fifth People's Hospital, Chengdu, Sichuan Province, China.
| | - Fang Yan
- Geriatric Diseases Institute of Chengdu, Department of Geriatrics, Chengdu Fifth People's Hospital, Chengdu, Sichuan Province, China; Geriatric Diseases Institute of Chengdu, Department of Intensive Care Medicine, Chengdu Fifth People's Hospital, Chengdu, Sichuan Province, China; Center for Medicine Research and Translation, Chengdu Fifth People's Hospital, Chengdu, Sichuan Province, China.
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Pitts SC, Schlom J, Donahue RN. Soluble immune checkpoints: implications for cancer prognosis and response to immune checkpoint therapy and conventional therapies. J Exp Clin Cancer Res 2024; 43:155. [PMID: 38822401 PMCID: PMC11141022 DOI: 10.1186/s13046-024-03074-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: 03/15/2024] [Accepted: 05/19/2024] [Indexed: 06/03/2024] Open
Abstract
Longitudinal sampling of tumor tissue from patients with solid cancers, aside from melanoma and a few other cases, is often unfeasible, and thus may not capture the plasticity of interactions between the tumor and immune system under selective pressure of a given therapy. Peripheral blood analyses provide salient information about the human peripheral immunome while offering technical and practical advantages over traditional tumor biopsies, and should be utilized where possible alongside interrogation of the tumor. Some common blood-based biomarkers used to study the immune response include immune cell subsets, circulating tumor DNA, and protein analytes such as cytokines. With the recent explosion of immune checkpoint inhibitors (ICI) as a modality of treatment in multiple cancer types, soluble immune checkpoints have become a relevant area of investigation for peripheral immune-based biomarkers. However, the exact functions of soluble immune checkpoints and their roles in cancer for the most part remain unclear. This review discusses current literature on the production, function, and expression of nine soluble immune checkpoints - sPD-L1, sPD-1, sCTLA4, sCD80, sTIM3, sLAG3, sB7-H3, sBTLA, and sHVEM - in patients with solid tumors, and explores their role as biomarkers of response to ICI as well as to conventional therapies (chemotherapy, radiotherapy, targeted therapy, and surgery) in cancer patients.
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Affiliation(s)
- Stephanie C Pitts
- Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Jeffrey Schlom
- Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
| | - Renee N Donahue
- Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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Cattaneo G, Ventin M, Arya S, Kontos F, Michelakos T, Sekigami Y, Cai L, Villani V, Sabbatino F, Chen F, Sadagopan A, Deshpande V, Moore PA, Ting DT, Bardeesy N, Wang X, Ferrone S, Ferrone CR. Interplay between B7-H3 and HLA class I in the clinical course of pancreatic ductal adenocarcinoma. Cancer Lett 2024; 587:216713. [PMID: 38364961 PMCID: PMC11146152 DOI: 10.1016/j.canlet.2024.216713] [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: 10/17/2023] [Revised: 01/16/2024] [Accepted: 02/05/2024] [Indexed: 02/18/2024]
Abstract
Human leukocyte antigen (HLA) class I defects are associated with cancer progression. However, their prognostic significance is controversial and may be modulated by immune checkpoints. Here, we investigated whether the checkpoint B7-H3 modulates the relationship between HLA class I and pancreatic ductal adenocarcinoma (PDAC) prognosis. PDAC tumors were analyzed for the expression of B7-H3, HLA class I, HLA class II molecules, and for the presence of tumor-infiltrating immune cells. We observed defective HLA class I and HLA class II expressions in 75% and 59% of PDAC samples, respectively. HLA class I and B7-H3 expression were positively related at mRNA and protein level, potentially because of shared regulation by RELA, a sub-unit of NF-kB. High B7-H3 expression and low CD8+ T cell density were indicators of poor survival, while HLA class I was not. Defective HLA class I expression was associated with unfavorable survival only in patients with low B7-H3 expression. Favorable survival was observed only when HLA class I expression was high and B7-H3 expression low. Our results provide the rationale for targeting B7-H3 in patients with PDAC tumors displaying high HLA class I levels.
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Affiliation(s)
- Giulia Cattaneo
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States. https://twitter.com/GCattaneoPhD
| | - Marco Ventin
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
| | - Shahrzad Arya
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
| | - Filippos Kontos
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
| | - Theodoros Michelakos
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
| | - Yurie Sekigami
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
| | - Lei Cai
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
| | - Vincenzo Villani
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
| | - Francesco Sabbatino
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
| | | | - Ananthan Sadagopan
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
| | - Vikram Deshpande
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
| | | | - David T Ting
- MassGeneral Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
| | - Nabeel Bardeesy
- MassGeneral Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
| | - Xinhui Wang
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
| | - Soldano Ferrone
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
| | - Cristina R Ferrone
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States; Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, United States.
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Varghese E, Samuel SM, Brockmueller A, Shakibaei M, Kubatka P, Büsselberg D. B7-H3 at the crossroads between tumor plasticity and colorectal cancer progression: a potential target for therapeutic intervention. Cancer Metastasis Rev 2024; 43:115-133. [PMID: 37768439 PMCID: PMC11016009 DOI: 10.1007/s10555-023-10137-8] [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: 07/12/2023] [Accepted: 09/07/2023] [Indexed: 09/29/2023]
Abstract
B7-H3 (B7 homology 3 protein) is an important transmembrane immunoregulatory protein expressed in immune cells, antigen-presenting cells, and tumor cells. Studies reveal a multifaceted role of B7-H3 in tumor progression by modulating various cancer hallmarks involving angiogenesis, immune evasion, and tumor microenvironment, and it is also a promising candidate for cancer immunotherapy. In colorectal cancer (CRC), B7-H3 has been associated with various aspects of disease progression, such as evasion of tumor immune surveillance, tumor-node metastasis, and poor prognosis. Strategies to block or interfere with B7-H3 in its immunological and non-immunological functions are under investigation. In this study, we explore the role of B7-H3 in tumor plasticity, emphasizing tumor glucose metabolism, angiogenesis, epithelial-mesenchymal transition, cancer stem cells, apoptosis, and changing immune signatures in the tumor immune landscape. We discuss how B7-H3-induced tumor plasticity contributes to immune evasion, metastasis, and therapy resistance. Furthermore, we delve into the most recent advancements in targeting B7-H3-based tumor immunotherapy as a potential approach to CRC treatment.
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Affiliation(s)
- Elizabeth Varghese
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, P.O. Box 24144, Doha, Qatar
| | - Samson Mathews Samuel
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, P.O. Box 24144, Doha, Qatar
| | - Aranka Brockmueller
- Chair of Vegetative Anatomy, Institute of Anatomy, Faculty of Medicine, Ludwig-Maximilians-University Munich, Pettenkoferstr. 11, 80336, Munich, Germany
| | - Mehdi Shakibaei
- Chair of Vegetative Anatomy, Institute of Anatomy, Faculty of Medicine, Ludwig-Maximilians-University Munich, Pettenkoferstr. 11, 80336, Munich, Germany
| | - Peter Kubatka
- Department of Histology and Embryology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Mala Hora 4, 036 01, Martin, Slovakia
| | - Dietrich Büsselberg
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, P.O. Box 24144, Doha, Qatar.
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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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11
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Zhang H, Zhu M, Zhao A, Shi T, Xi Q. B7-H3 regulates anti-tumor immunity and promotes tumor development in colorectal cancer. Biochim Biophys Acta Rev Cancer 2024; 1879:189031. [PMID: 38036107 DOI: 10.1016/j.bbcan.2023.189031] [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: 09/19/2023] [Revised: 11/20/2023] [Accepted: 11/23/2023] [Indexed: 12/02/2023]
Abstract
Colorectal cancer (CRC) is a common malignant tumor of the gastrointestinal tract and one of the most common causes of cancer-related deaths worldwide. Immune checkpoint inhibitors have become a milestone in many cancer treatments with significant curative effects. However, its therapeutic effect on colorectal cancer is still limited. B7-H3 is a novel immune checkpoint molecule of the B7/CD28 family and is overexpressed in a variety of solid tumors including colorectal cancer. B7-H3 was considered as a costimulatory molecule that promotes anti-tumor immunity. However, more and more studies support that B7-H3 is a co-inhibitory molecule and plays an important immunosuppressive role in colorectal cancer. Meanwhile, B7-H3 promoted metabolic reprogramming, invasion and metastasis, and chemoresistance in colorectal cancer. Therapies targeting B7-H3, including monoclonal antibodies, antibody drug conjugations, and chimeric antigen receptor T cells, have great potential to improve the prognosis of colorectal cancer patients.
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Affiliation(s)
- Huan Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Mengxin Zhu
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Anjing Zhao
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Tongguo Shi
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
| | - Qinhua Xi
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
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12
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Li HY, Chen YL, Deng XN, Li HH, Tan J, Liu GJ, Zheng YJ, Pei M, Peng KT, Yue LL, Chen XJ, Liu Y, Zhao YS, Wang CH. Bispecific antibody targeting both B7-H3 and PD-L1 exhibits superior antitumor activities. Acta Pharmacol Sin 2023; 44:2322-2330. [PMID: 37328649 PMCID: PMC10618207 DOI: 10.1038/s41401-023-01118-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Accepted: 05/28/2023] [Indexed: 06/18/2023]
Abstract
Clinical application of PD-1 and PD-L1 monoclonal antibodies (mAbs) is hindered by their relatively low response rates and the occurrence of drug resistance. Co-expression of B7-H3 with PD-L1 has been found in various solid tumors, and combination therapies that target both PD-1/PD-L1 and B7-H3 pathways may provide additional therapeutic benefits. Up to today, however, no bispecific antibodies targeting both PD-1 and B7-H3 have reached the clinical development stage. In this study, we generated a stable B7-H3×PD-L1 bispecific antibody (BsAb) in IgG1-VHH format by coupling a humanized IgG1 mAb against PD-L1 with a humanized camelus variable domain of the heavy-chain of heavy-chain antibody (VHH) against human B7-H3. The BsAb exhibited favorable thermostability, efficient T cell activation, IFN-γ production, and antibody-dependent cell-mediated cytotoxicity (ADCC). In a PBMC humanized A375 xenogeneic tumor model, treatment with BsAb (10 mg/kg, i.p., twice a week for 6 weeks) showed enhanced antitumor activities compared to monotherapies and, to some degree, combination therapies. Our results suggest that targeting both PD-1 and B7-H3 with BsAbs increases their specificities to B7-H3 and PD-L1 double-positive tumors and induces a synergetic effect. We conclude that B7-H3×PD-L1 BsAb is favored over mAbs and possibly combination therapies in treating B7-H3 and PD-L1 double-positive tumors.
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Affiliation(s)
- Hua-Ying Li
- Shanghai Mabstone Biotechnologies, Ltd., Shanghai, 201203, China
- School of Life Science and Bio-Pharmaceutics, Shenyang Pharmaceutical University, Shenyang, 110016, China
- Biotherapeutics Discovery Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Yi-Li Chen
- Shanghai Mabstone Biotechnologies, Ltd., Shanghai, 201203, China.
| | - Xiang-Nan Deng
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Huan-Huan Li
- Shanghai Mabstone Biotechnologies, Ltd., Shanghai, 201203, China
| | - Jie Tan
- Shanghai Mabstone Biotechnologies, Ltd., Shanghai, 201203, China
| | - Guo-Jian Liu
- Dartsbio Pharmaceuticals, Ltd., Zhongshan, 528400, China
| | - Yu-Juan Zheng
- Biotherapeutics Discovery Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Min Pei
- Shanghai Mabstone Biotechnologies, Ltd., Shanghai, 201203, China
- Institute of Biomedicine & Department of Cell Biology, Jinan University, National Engineering Research Center of Genetic Medicine, Guangzhou, 510632, China
| | - Kai-Ting Peng
- Biotherapeutics Discovery Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Li-Li Yue
- Biotherapeutics Discovery Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, 211198, China
| | - Xiao-Jia Chen
- Institute of Biomedicine & Department of Cell Biology, Jinan University, National Engineering Research Center of Genetic Medicine, Guangzhou, 510632, China
| | - Yu Liu
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, 211198, China
| | - Yong-Shan Zhao
- School of Life Science and Bio-Pharmaceutics, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Chun-He Wang
- Biotherapeutics Discovery Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
- Dartsbio Pharmaceuticals, Ltd., Zhongshan, 528400, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- Institute of Biomedicine & Department of Cell Biology, Jinan University, National Engineering Research Center of Genetic Medicine, Guangzhou, 510632, China.
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, 211198, China.
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13
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Kovaleva OV, Gratchev AN, Sokolov NY, Maslennikov VV, Kuzmin YB, Gershtein ES, Alferov AA, Mamedli ZZ, Stilidi IS, Kushlinskii NE. Soluble B7-H3 in Colorectal Cancer. Bull Exp Biol Med 2023; 176:87-90. [PMID: 38085395 DOI: 10.1007/s10517-023-05972-2] [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: 04/13/2023] [Indexed: 12/19/2023]
Abstract
We present the results of comparative ELISA of the concentration of soluble form of immunity checkpoint B7-H3 (sB7-H3) in the serum of patients with colorectal cancer (CRC) at different stages before treatment and healthy control donors. The analysis revealed a statistically significant difference between the median levels of sB7-H3 in the blood serum of CRC patients (19.66 ng/ml) and healthy donors (16.76 ng/ml) (p=0.0025). ROC analysis showed 62.9% sensitivity and 56.7% specificity for CRC patients (cut-off 17.62 ng/ml; p=0.0028). An association of sB7-H3 levels with tumor progression was revealed. We demonstrated that sB7-H3 levels were significantly lower in patients with regional metastases than in patients without metastases (p=0.039) and that sB7-H3 concentration tends to decrease at the late stages of the disease. Thus, high serum level of sB7-H3 in CRC patients can be a favorable prognostic factor in future.
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Affiliation(s)
- O V Kovaleva
- N. N. Blokhin National Medical Research Center of Oncology, Ministry of Health of the Russian Federation, Moscow, Russia.
| | - A N Gratchev
- N. N. Blokhin National Medical Research Center of Oncology, Ministry of Health of the Russian Federation, Moscow, Russia
| | - N Yu Sokolov
- N. N. Blokhin National Medical Research Center of Oncology, Ministry of Health of the Russian Federation, Moscow, Russia
| | - V V Maslennikov
- N. N. Blokhin National Medical Research Center of Oncology, Ministry of Health of the Russian Federation, Moscow, Russia
| | - Yu B Kuzmin
- N. N. Blokhin National Medical Research Center of Oncology, Ministry of Health of the Russian Federation, Moscow, Russia
| | - E S Gershtein
- N. N. Blokhin National Medical Research Center of Oncology, Ministry of Health of the Russian Federation, Moscow, Russia
| | - A A Alferov
- N. N. Blokhin National Medical Research Center of Oncology, Ministry of Health of the Russian Federation, Moscow, Russia
| | - Z Z Mamedli
- N. N. Blokhin National Medical Research Center of Oncology, Ministry of Health of the Russian Federation, Moscow, Russia
| | - I S Stilidi
- N. N. Blokhin National Medical Research Center of Oncology, Ministry of Health of the Russian Federation, Moscow, Russia
| | - N E Kushlinskii
- N. N. Blokhin National Medical Research Center of Oncology, Ministry of Health of the Russian Federation, Moscow, Russia
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14
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Shin SH, Ju EJ, Park J, Ko EJ, Kwon MR, Lee HW, Son GW, Park YY, Kim YJ, Song SY, Lee S, Seo BS, Song JA, Lim S, Jung D, Kim S, Lee H, Park SS, Jeong SY, Choi EK. ITC-6102RO, a novel B7-H3 antibody-drug conjugate, exhibits potent therapeutic effects against B7-H3 expressing solid tumors. Cancer Cell Int 2023; 23:172. [PMID: 37596639 PMCID: PMC10439577 DOI: 10.1186/s12935-023-02991-x] [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: 05/23/2023] [Accepted: 07/12/2023] [Indexed: 08/20/2023] Open
Abstract
BACKGROUND The B7-H3 protein, encoded by the CD276 gene, is a member of the B7 family of proteins and a transmembrane glycoprotein. It is highly expressed in various solid tumors, such as lung and breast cancer, and has been associated with limited expression in normal tissues and poor clinical outcomes across different malignancies. Additionally, B7-H3 plays a crucial role in anticancer immune responses. Antibody-drug conjugates (ADCs) are a promising therapeutic modality, utilizing antibodies targeting tumor antigens to selectively and effectively deliver potent cytotoxic agents to tumors. METHODS In this study, we demonstrate the potential of a novel B7-H3-targeting ADC, ITC-6102RO, for B7-H3-targeted therapy. ITC-6102RO was developed and conjugated with dHBD, a soluble derivative of pyrrolobenzodiazepine (PBD), using Ortho Hydroxy-Protected Aryl Sulfate (OHPAS) linkers with high biostability. We assessed the cytotoxicity and internalization of ITC-6102RO in B7-H3 overexpressing cell lines in vitro and evaluated its anticancer efficacy and mode of action in B7-H3 overexpressing cell-derived and patient-derived xenograft models in vivo. RESULTS ITC-6102RO inhibited cell viability in B7-H3-positive lung and breast cancer cell lines, inducing cell cycle arrest in the S phase, DNA damage, and apoptosis in vitro. The binding activity and selectivity of ITC-6102RO with B7-H3 were comparable to those of the unconjugated anti-B7-H3 antibody. Furthermore, ITC-6102RO proved effective in B7-H3-positive JIMT-1 subcutaneously xenografted mice and exhibited a potent antitumor effect on B7-H3-positive lung cancer patient-derived xenograft (PDX) models. The mode of action, including S phase arrest and DNA damage induced by dHBD, was confirmed in JIMT-1 tumor tissues. CONCLUSIONS Our preclinical data indicate that ITC-6102RO is a promising therapeutic agent for B7-H3-targeted therapy. Moreover, we anticipate that OHPAS linkers will serve as a valuable platform for developing novel ADCs targeting a wide range of targets.
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Affiliation(s)
- Seol Hwa Shin
- Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea
- Asan Institute for Life Sciences, ASAN Medical Center, Seoul, 05505, Republic of Korea
- Asan Preclinical Evaluation Center for Cancer Therapeutics, ASAN Medical Center, Seoul, 05505, Republic of Korea
| | - Eun Jin Ju
- Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea
- Asan Institute for Life Sciences, ASAN Medical Center, Seoul, 05505, Republic of Korea
- Asan Preclinical Evaluation Center for Cancer Therapeutics, ASAN Medical Center, Seoul, 05505, Republic of Korea
| | - Jin Park
- Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea
- Asan Institute for Life Sciences, ASAN Medical Center, Seoul, 05505, Republic of Korea
- Asan Preclinical Evaluation Center for Cancer Therapeutics, ASAN Medical Center, Seoul, 05505, Republic of Korea
| | - Eun Jung Ko
- Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea
- Asan Institute for Life Sciences, ASAN Medical Center, Seoul, 05505, Republic of Korea
- Asan Preclinical Evaluation Center for Cancer Therapeutics, ASAN Medical Center, Seoul, 05505, Republic of Korea
| | - Mi Ri Kwon
- Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea
- Asan Institute for Life Sciences, ASAN Medical Center, Seoul, 05505, Republic of Korea
- Asan Preclinical Evaluation Center for Cancer Therapeutics, ASAN Medical Center, Seoul, 05505, Republic of Korea
| | - Hye Won Lee
- Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea
- Asan Institute for Life Sciences, ASAN Medical Center, Seoul, 05505, Republic of Korea
- Asan Preclinical Evaluation Center for Cancer Therapeutics, ASAN Medical Center, Seoul, 05505, Republic of Korea
| | - Ga Won Son
- Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea
- Asan Institute for Life Sciences, ASAN Medical Center, Seoul, 05505, Republic of Korea
- Asan Preclinical Evaluation Center for Cancer Therapeutics, ASAN Medical Center, Seoul, 05505, Republic of Korea
| | - Yun-Yong Park
- Department of Life Science, Chung-Ang University, Seoul, 06974, Republic of Korea
| | - Yeon Joo Kim
- Department of Radiation Oncology, ASAN Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea
| | - Si Yeol Song
- Department of Radiation Oncology, ASAN Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea
| | - Sangkwang Lee
- IntoCell Inc, 101, Sinildong-ro, Daedeok-gu, Daejeon, 34324, Republic of Korea
| | - Beom Seok Seo
- IntoCell Inc, 101, Sinildong-ro, Daedeok-gu, Daejeon, 34324, Republic of Korea
| | - Jin-A Song
- IntoCell Inc, 101, Sinildong-ro, Daedeok-gu, Daejeon, 34324, Republic of Korea
| | - Sangbin Lim
- IntoCell Inc, 101, Sinildong-ro, Daedeok-gu, Daejeon, 34324, Republic of Korea
| | - Doohwan Jung
- IntoCell Inc, 101, Sinildong-ro, Daedeok-gu, Daejeon, 34324, Republic of Korea
| | - Sunyoung Kim
- IntoCell Inc, 101, Sinildong-ro, Daedeok-gu, Daejeon, 34324, Republic of Korea
| | - Hyangsook Lee
- Department of Radiation Oncology, ASAN Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea
| | - Seok Soon Park
- Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea.
- Asan Institute for Life Sciences, ASAN Medical Center, Seoul, 05505, Republic of Korea.
- Asan Preclinical Evaluation Center for Cancer Therapeutics, ASAN Medical Center, Seoul, 05505, Republic of Korea.
| | - Seong-Yun Jeong
- Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea.
- Asan Institute for Life Sciences, ASAN Medical Center, Seoul, 05505, Republic of Korea.
- Asan Preclinical Evaluation Center for Cancer Therapeutics, ASAN Medical Center, Seoul, 05505, Republic of Korea.
| | - Eun Kyung Choi
- Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea.
- Asan Institute for Life Sciences, ASAN Medical Center, Seoul, 05505, Republic of Korea.
- Asan Preclinical Evaluation Center for Cancer Therapeutics, ASAN Medical Center, Seoul, 05505, Republic of Korea.
- Department of Radiation Oncology, ASAN Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea.
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15
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Urbiola-Salvador V, Jabłońska A, Miroszewska D, Huang Q, Duzowska K, Drężek-Chyła K, Zdrenka M, Śrutek E, Szylberg Ł, Jankowski M, Bała D, Zegarski W, Nowikiewicz T, Makarewicz W, Adamczyk A, Ambicka A, Przewoźnik M, Harazin-Lechowicz A, Ryś J, Filipowicz N, Piotrowski A, Dumanski JP, Li B, Chen Z. Plasma protein changes reflect colorectal cancer development and associated inflammation. Front Oncol 2023; 13:1158261. [PMID: 37228491 PMCID: PMC10203952 DOI: 10.3389/fonc.2023.1158261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Accepted: 04/05/2023] [Indexed: 05/27/2023] Open
Abstract
Introduction Colorectal cancer (CRC) is the third most common malignancy and the second leading cause of death worldwide. Efficient non-invasive blood-based biomarkers for CRC early detection and prognosis are urgently needed. Methods To identify novel potential plasma biomarkers, we applied a proximity extension assay (PEA), an antibody-based proteomics strategy to quantify the abundance of plasma proteins in CRC development and cancer-associated inflammation from few μL of plasma sample. Results Among the 690 quantified proteins, levels of 202 plasma proteins were significantly changed in CRC patients compared to age-and-sex-matched healthy subjects. We identified novel protein changes involved in Th17 activity, oncogenic pathways, and cancer-related inflammation with potential implications in the CRC diagnosis. Moreover, the interferon γ (IFNG), interleukin (IL) 32, and IL17C were identified as associated with the early stages of CRC, whereas lysophosphatidic acid phosphatase type 6 (ACP6), Fms-related tyrosine kinase 4 (FLT4), and MANSC domain-containing protein 1 (MANSC1) were correlated with the late-stages of CRC. Discussion Further study to characterize the newly identified plasma protein changes from larger cohorts will facilitate the identification of potential novel diagnostic, prognostic biomarkers for CRC.
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Affiliation(s)
- Víctor Urbiola-Salvador
- Intercollegiate Faculty of Biotechnology of University of Gdańsk and Medical University of Gdańsk, University of Gdańsk, Gdańsk, Poland
| | - Agnieszka Jabłońska
- Intercollegiate Faculty of Biotechnology of University of Gdańsk and Medical University of Gdańsk, University of Gdańsk, Gdańsk, Poland
| | - Dominika Miroszewska
- Intercollegiate Faculty of Biotechnology of University of Gdańsk and Medical University of Gdańsk, University of Gdańsk, Gdańsk, Poland
| | - Qianru Huang
- Center for Immune-Related Diseases at Shanghai Institute of Immunology, Department of Respiratory and Critical Care Medicine of Ruijin Hospital, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | | | | | - Marek Zdrenka
- Department of Tumor Pathology and Pathomorphology, Oncology Center−Prof. Franciszek Łukaszczyk Memorial Hospital, Bydgoszcz, Poland
| | - Ewa Śrutek
- Department of Tumor Pathology and Pathomorphology, Oncology Center−Prof. Franciszek Łukaszczyk Memorial Hospital, Bydgoszcz, Poland
| | - Łukasz Szylberg
- Department of Tumor Pathology and Pathomorphology, Oncology Center−Prof. Franciszek Łukaszczyk Memorial Hospital, Bydgoszcz, Poland
- Department of Obstetrics, Gynaecology and Oncology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Bydgoszcz, Poland
| | - Michał Jankowski
- Surgical Oncology, Ludwik Rydygier’s Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in ToruńSurgical Oncology, Ludwik Rydygier’s Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Toruń, Poland
- Department of Surgical Oncology, Oncology Center−Prof. Franciszek Łukaszczyk Memorial Hospital, Bydgoszcz, Poland
| | - Dariusz Bała
- Surgical Oncology, Ludwik Rydygier’s Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in ToruńSurgical Oncology, Ludwik Rydygier’s Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Toruń, Poland
- Department of Surgical Oncology, Oncology Center−Prof. Franciszek Łukaszczyk Memorial Hospital, Bydgoszcz, Poland
| | - Wojciech Zegarski
- Surgical Oncology, Ludwik Rydygier’s Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in ToruńSurgical Oncology, Ludwik Rydygier’s Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Toruń, Poland
- Department of Surgical Oncology, Oncology Center−Prof. Franciszek Łukaszczyk Memorial Hospital, Bydgoszcz, Poland
| | - Tomasz Nowikiewicz
- Surgical Oncology, Ludwik Rydygier’s Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in ToruńSurgical Oncology, Ludwik Rydygier’s Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Toruń, Poland
- Department of Breast Cancer and Reconstructive Surgery, Oncology Center−Prof. Franciszek Łukaszczyk Memorial Hospital, Bydgoszcz, Poland
| | - Wojciech Makarewicz
- Clinic of General and Oncological Surgery, Specialist Hospital of Kościerzyna, Kościerzyna, Poland
| | - Agnieszka Adamczyk
- Department of Tumor Pathology, Maria Skłodowska-Curie National Research Institute of Oncology, Kraków, Poland
| | - Aleksandra Ambicka
- Department of Tumor Pathology, Maria Skłodowska-Curie National Research Institute of Oncology, Kraków, Poland
| | - Marcin Przewoźnik
- Department of Tumor Pathology, Maria Skłodowska-Curie National Research Institute of Oncology, Kraków, Poland
| | - Agnieszka Harazin-Lechowicz
- Department of Tumor Pathology, Maria Skłodowska-Curie National Research Institute of Oncology, Kraków, Poland
| | - Janusz Ryś
- Department of Tumor Pathology, Maria Skłodowska-Curie National Research Institute of Oncology, Kraków, Poland
| | | | | | - Jan P. Dumanski
- 3P-Medicine Laboratory, Medical University of Gdańsk, Gdańsk, Poland
- Department of Immunology, Genetics and Pathology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden
- Department of Biology and Pharmaceutical Botany, Medical University of Gdańsk, Gdańsk, Poland
| | - Bin Li
- Center for Immune-Related Diseases at Shanghai Institute of Immunology, Department of Respiratory and Critical Care Medicine of Ruijin Hospital, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhi Chen
- Intercollegiate Faculty of Biotechnology of University of Gdańsk and Medical University of Gdańsk, University of Gdańsk, Gdańsk, Poland
- Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland
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16
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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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17
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Gan C, Li M, Lu Y, Peng G, Li W, Wang H, Peng Y, Hu Q, Wei W, Wang F, Liu L, Zhao Q. SPOCK1 and POSTN are valuable prognostic biomarkers and correlate with tumor immune infiltrates in colorectal cancer. BMC Gastroenterol 2023; 23:4. [PMID: 36611136 PMCID: PMC9826581 DOI: 10.1186/s12876-022-02621-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Accepted: 12/15/2022] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND Immune cells and stromal cells in the tumor microenvironment play a vital role in the progression of colorectal cancer (CRC). The study aimed to screen valuable prognostic biomarkers in CRC based on stromal and immune scores. METHOD The ESTIMATE algorithm was used to calculate the immune and stromal scores of CRC samples in TCGA. Then samples were divided into high and low score groups based on the median value of the scores. Differentially expressed genes (DEGs) associated with immune and stromal scores were screened. WGCNA and univariate COX regression analysis were performed to further identify key prognostic genes. Analysis of scRNA-seq for CRC was used for verifying the main source of the key genes. The prognostic value of they was validated based on The Gene Expression Profiling Interactive Analysis and GSE17536 dataset. TIMER and CIBERSORT algorithms were applied to analyze the correlations among key genes and tumor-infiltrating immune cells. Several pairs of colon cancer tissue were used to be proven. RESULT 1314 upregulated and 4 downregulated genes were identified, which were significantly enriched in immune-related biological processes and pathways. Among these DEGs, SPOCK1 and POSTN were identified as key prognostic genes and mainly expressed in cancer-associated fibroblasts for CRC. High expression of SPCOK1 and POSTN was associated with advanced clinical stage, T stage, N stage, and poor prognosis of CRC. The results from CIBERSORT and TIMER revealed that SPOCK1 and POSTN were associated with tumor-infiltrating immune cells, especially macrophages and neutrophils. Meanwhile, in several pairs of human colorectal tissue samples, SPOK1 and POSTN were found to be significantly overexpressed in colorectal tissue compared with para-cancer tissue, and macrophage surface markers CD68 (co-expressed by M1 and M2 macrophages) and CD206 (M2-specific macrophage expression) were also overexpressed in cancer tissue. Besides, SPOCK1 and POSTN expression were positively correlated with the expression of immune checkpoints. CONCLUSION Collectively, our results indicate that SPOCK1 and POSTN associated with CAF may be novel prognostic biomarkers in CRC and correlate with immune infiltrates.
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Affiliation(s)
- Caiqin Gan
- grid.413247.70000 0004 1808 0969Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430000 China ,grid.413247.70000 0004 1808 0969Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, 430000 China
| | - Mengting Li
- grid.413247.70000 0004 1808 0969Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430000 China ,grid.413247.70000 0004 1808 0969Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, 430000 China
| | - Yuanyuan Lu
- grid.413247.70000 0004 1808 0969Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430000 China ,grid.413247.70000 0004 1808 0969Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, 430000 China
| | - Ganjing Peng
- grid.413247.70000 0004 1808 0969Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430000 China ,grid.413247.70000 0004 1808 0969Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, 430000 China
| | - Wenjie Li
- grid.413247.70000 0004 1808 0969Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430000 China ,grid.413247.70000 0004 1808 0969Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, 430000 China
| | - Haizhou Wang
- grid.413247.70000 0004 1808 0969Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430000 China ,grid.413247.70000 0004 1808 0969Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, 430000 China
| | - Yanan Peng
- grid.413247.70000 0004 1808 0969Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430000 China ,grid.413247.70000 0004 1808 0969Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, 430000 China
| | - Qian Hu
- grid.413247.70000 0004 1808 0969Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430000 China ,grid.413247.70000 0004 1808 0969Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, 430000 China
| | - Wanhui Wei
- grid.413247.70000 0004 1808 0969Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430000 China ,grid.413247.70000 0004 1808 0969Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, 430000 China
| | - Fan Wang
- grid.413247.70000 0004 1808 0969Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430000 China ,grid.413247.70000 0004 1808 0969Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, 430000 China
| | - Lan Liu
- grid.413247.70000 0004 1808 0969Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430000 China ,grid.413247.70000 0004 1808 0969Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, 430000 China
| | - Qiu Zhao
- grid.413247.70000 0004 1808 0969Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430000 China ,grid.413247.70000 0004 1808 0969Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, 430000 China
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18
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Razi Soofiyani S, Minaei Beirami S, Hosseini K, Mohammadi Nasr M, Ranjbar M, Forouhandeh H, Tarhriz V, Sadeghi M. Revisiting Inhibition Effects of miR-28 as a Metastasis Suppressor in Gastrointestinal Cancers. Microrna 2023; 12:131-142. [PMID: 37073155 DOI: 10.2174/2211536612666230413125126] [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: 05/11/2022] [Revised: 11/09/2022] [Accepted: 01/20/2023] [Indexed: 04/20/2023]
Abstract
MicroRNAs are critical epigenetic regulators that can be used as diagnostic, prognostic, and therapeutic biomarkers for the treatment of various diseases, including gastrointestinal cancers, among a variety of cellular and molecular biomarkers. MiRNAs have also shown oncogenic or tumor suppressor roles in tumor tissue and other cell types. Studies showed that the dysregulation of miR-28 is involved in cell growth and metastasis of gastrointestinal cancers. MiR-28 plays a key role in controlling the physiological processes of cancer cells including growth and proliferation, migration, invasion, apoptosis, and metastasis. Therefore, miR-28 expression patterns can be used to distinguish patient subgroups. Based on the previous studies, miR-28 expression can be a suitable biomarker to detect tumor size and predict histological grade metastasis. In this review, we summarize the inhibitory effects of miR-28 as a metastasis suppressor in gastrointestinal cancers. miR-28 plays a role as a tumor suppressor in gastrointestinal cancers by regulating cancer cell growth, cell differentiation, angiogenesis, and metastasis. As a result, using it as a prognostic, diagnostic, and therapeutic biomarker in the treatment of gastrointestinal cancers can be a way to solve the problems in this field.
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Affiliation(s)
- Saiedeh Razi Soofiyani
- Molecular Medicine Research Center, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
- Clinical Research Development Unit, Sina Educational, Research and Treatment Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sohrab Minaei Beirami
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Kamran Hosseini
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
- Faculty of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mina Mohammadi Nasr
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Molecular Medicine, Faculty of Advanced Medical Sciences. Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maryam Ranjbar
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Haleh Forouhandeh
- Molecular Medicine Research Center, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Vahideh Tarhriz
- Molecular Medicine Research Center, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammadreza Sadeghi
- Department of Molecular Medicine, Faculty of Advanced Medical Sciences. Tabriz University of Medical Sciences, Tabriz, Iran
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19
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Wu C, Yang J, Ding R, Li X, Yang Z, Zhu M, Liu Z. Identification of a costimulatory molecule-based signature to predict prognostic risk of pancreatic adenocarcinoma. ALL LIFE 2022. [DOI: 10.1080/26895293.2022.2090450] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022] Open
Affiliation(s)
- Chao Wu
- Department of Oncology, Chinese PLA General Hospital, Beijing, People’s Republic of China
| | - Jingyue Yang
- Department of Oncology, Xijing Hospital, Air Force Military Medical University, Xi’an, People’s Republic of China
| | - Rui Ding
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Military Medical University, Xi’an, People’s Republic of China
| | - Xiao Li
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Military Medical University, Xi’an, People’s Republic of China
| | - Zhi Yang
- The IVD Medical Marketing Department, 3D Medicines Inc., Shanghai, People’s Republic of China
| | - Min Zhu
- Department of Oncology, The Fifth medical center, Chinese PLA General Hospital, Beijing, People’s Republic of China
| | - Zhengcai Liu
- Department of Hepatopancreatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, People’s Republic of China
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20
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Abstract
Since B7-H3 is overexpressed or amplified in many types of solid tumors with a restricted expression in the normal tissues, it has been an emerging immunotherapeutic target for solid tumors. This review will focus on the structural designs of developing chimeric antigen receptors (CARs) targeting B7-H3. The expression, receptor, and function of the B7-H3, as well as a short overview of B7-H3-targeted monoclonal antibody therapy, are discussed. Finally, a detailed summary of B7-H3 redirected CAR-T and CAR-NK cell approaches utilized in preclinical models and currently ongoing or completed clinical trials are presented. It has been demonstrated that B7-H3-targeted CAR-based cell therapies were safe in initial trials, but their efficacy was limited. Employing the local delivery routes, the introduction of novel modifications promoting CAR-T persistence, and combined treatment with other standard therapies could improve the efficacy of B7-H3-targeted CAR-T cell therapy against solid tumors.
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Affiliation(s)
- Guangfei Li
- ENT institute and Department of Otorhinolaryngology, Eye & ENT Hospital, Fudan University, Shanghai, China
| | - Haopeng Wang
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China
| | - Haitao Wu
- ENT institute and Department of Otorhinolaryngology, Eye & ENT Hospital, Fudan University, Shanghai, China
| | - Jian Chen
- ENT institute and Department of Otorhinolaryngology, Eye & ENT Hospital, Fudan University, Shanghai, China
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21
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Targeted Therapy of B7 Family Checkpoints as an Innovative Approach to Overcome Cancer Therapy Resistance: A Review from Chemotherapy to Immunotherapy. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27113545. [PMID: 35684481 PMCID: PMC9182385 DOI: 10.3390/molecules27113545] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Revised: 05/24/2022] [Accepted: 05/25/2022] [Indexed: 11/17/2022]
Abstract
It is estimated that there were 18.1 million cancer cases worldwide in 2018, with about 9 million deaths. Proper diagnosis of cancer is essential for its effective treatment because each type of cancer requires a specific treatment procedure. Cancer therapy includes one or more approaches such as surgery, radiotherapy, chemotherapy, and immunotherapy. In recent years, immunotherapy has received much attention and immune checkpoint molecules have been used to treat several cancers. These molecules are involved in regulating the activity of T lymphocytes. Accumulated evidence shows that targeting immune checkpoint regulators like PD-1/PD-L1 and CTLA-4 are significantly useful in treating cancers. According to studies, these molecules also have pivotal roles in the chemoresistance of cancer cells. Considering these findings, the combination of immunotherapy and chemotherapy can help to treat cancer with a more efficient approach. Among immune checkpoint molecules, the B7 family checkpoints have been studied in various cancer types such as breast cancer, myeloma, and lymphoma. In these cancers, they cause the cells to become resistant to the chemotherapeutic agents. Discovering the exact signaling pathways and selective targeting of these checkpoint molecules may provide a promising avenue to overcome cancer development and therapy resistance. Highlights: (1) The development of resistance to cancer chemotherapy or immunotherapy is the main obstacle to improving the outcome of these anti-cancer therapies. (2) Recent investigations have described the involvement of immune checkpoint molecules in the development of cancer therapy resistance. (3) In the present study, the molecular participation of the B7 immune checkpoint family in anticancer therapies has been highlighted. (4) Targeting these immune checkpoint molecules may be considered an efficient approach to overcoming this obstacle.
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22
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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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23
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Liu C, Zhang G, Xiang K, Kim Y, Lavoie RR, Lucien F, Wen T. Targeting the immune checkpoint B7-H3 for next-generation cancer immunotherapy. Cancer Immunol Immunother 2021; 71:1549-1567. [PMID: 34739560 DOI: 10.1007/s00262-021-03097-x] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Accepted: 10/21/2021] [Indexed: 12/12/2022]
Abstract
Immune checkpoint inhibitors (ICIs) for programmed death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) have become preferred treatment strategies for several advanced cancers. However, response rates for these treatments are limited, which encourages the search for new ICI candidates. Recent reports have underscored significant roles of B7 homolog 3 protein (B7-H3) in tumor immunity and disease progression. While its multifaceted roles are being elucidated, B7-H3 has already entered clinical trials as a therapeutic target. In this review, we overview the recent results of clinical trials evaluating the antitumor activity and safety of B7-H3 targeting drugs. On this basis, we also discuss the challenges and opportunities arising from the application of these drugs. Finally, we point out current gaps to address in the understanding of B7-H3 function and regulation in order to fully unleash the future clinical utility of B7-H3-based therapies for the treatment of cancer.
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Affiliation(s)
- Chuan Liu
- Department of Medical Oncology, Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, China
- Liaoning Province Clinical Research Center for Cancer, Shenyang, China
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, Shenyang, China
| | - Guangwei Zhang
- Smart Hospital Management Department, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Kanghui Xiang
- Department of Medical Oncology, Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, China
- Liaoning Province Clinical Research Center for Cancer, Shenyang, China
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, Shenyang, China
| | - Yohan Kim
- Department of Urology, Mayo Clinic, Rochester, MN, USA
| | | | | | - Ti Wen
- Department of Medical Oncology, Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, China.
- Liaoning Province Clinical Research Center for Cancer, Shenyang, China.
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, Shenyang, China.
- Department of Urology, Mayo Clinic, Rochester, MN, USA.
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24
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Zhang LY, Jin Y, Xia PH, Lin J, Ma JC, Li T, Liu ZQ, Xiang HL, Cheng C, Xu ZJ, Zhou H, Qian J. Integrated analysis reveals distinct molecular, clinical, and immunological features of B7-H3 in acute myeloid leukemia. Cancer Med 2021; 10:7831-7846. [PMID: 34562306 PMCID: PMC8559480 DOI: 10.1002/cam4.4284] [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: 01/09/2021] [Revised: 06/25/2021] [Accepted: 08/29/2021] [Indexed: 12/12/2022] Open
Abstract
The role of B7‐H3 in acute myeloid leukemia (AML) is not fully understood. Two previous studies investigating its expression and significances in AML are partially different. In this study, we aimed to systematically characterize the genomic and immune landscape in AML patients with altered B7‐H3 expression using multi‐omics data in the public domain. We found significantly increased B7‐H3 expression in AML compared to either other hematological malignancies or healthy controls. Clinically, high B7‐H3 expression was associated with old age, TP53 mutations, wild‐type WT1 and CEBPA, and the M3 and M5 FAB subtypes. Moreover, we observed that increased B7‐H3 expression correlated significantly with a poor outcome of AML patients in four independent datasets. Gene set enrichment analysis (GSEA) revealed the enrichment of the “EMT” oncogenic gene signatures in high B7‐H3 expressers. Further investigation suggested that B7‐H3 was more likely to be associated with immune‐suppressive cells (macrophages, neutrophils, dendritic cells, and Th17 cells). B7‐H3 was also positively associated with a number of checkpoint genes, such as VISTA (B7‐H5), CD80 (B7‐1), CD86 (B7‐2), and CD70. In summary, we uncovered distinct genomic and immunologic features associated with B7‐H3 expression in AML. This may lead to a better understanding of the molecular mechanisms underlying B7‐H3 dysregulation in AML and to the development of novel therapeutic strategies.
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Affiliation(s)
- Ling-Yi Zhang
- Laboratory Center, Affiliated People's Hospital of Jiangsu University, Jiangsu, China.,Zhenjiang Clinical Research Center of Hematology, Jiangsu, China
| | - Ye Jin
- Zhenjiang Clinical Research Center of Hematology, Jiangsu, China.,Department of Hematology, Affiliated People's Hospital of Jiangsu University, Jiangsu, China
| | - Pei-Hui Xia
- Laboratory Center, Affiliated People's Hospital of Jiangsu University, Jiangsu, China.,Zhenjiang Clinical Research Center of Hematology, Jiangsu, China
| | - Jiang Lin
- Laboratory Center, Affiliated People's Hospital of Jiangsu University, Jiangsu, China.,Zhenjiang Clinical Research Center of Hematology, Jiangsu, China
| | - Ji-Chun Ma
- Laboratory Center, Affiliated People's Hospital of Jiangsu University, Jiangsu, China.,Zhenjiang Clinical Research Center of Hematology, Jiangsu, China
| | - Ting Li
- Zhenjiang Clinical Research Center of Hematology, Jiangsu, China.,Department of Hematology, Affiliated People's Hospital of Jiangsu University, Jiangsu, China
| | - Zi-Qi Liu
- Zhenjiang Clinical Research Center of Hematology, Jiangsu, China.,Department of Hematology, Affiliated People's Hospital of Jiangsu University, Jiangsu, China
| | - He-Lin Xiang
- Zhenjiang Clinical Research Center of Hematology, Jiangsu, China.,Department of Hematology, Affiliated People's Hospital of Jiangsu University, Jiangsu, China
| | - Chen Cheng
- Laboratory Center, Affiliated People's Hospital of Jiangsu University, Jiangsu, China.,Zhenjiang Clinical Research Center of Hematology, Jiangsu, China
| | - Zi-Jun Xu
- Laboratory Center, Affiliated People's Hospital of Jiangsu University, Jiangsu, China.,Zhenjiang Clinical Research Center of Hematology, Jiangsu, China
| | - Hong Zhou
- School of Medical Science and Laboratory Medicine, Jiangsu University, Jiangsu, China
| | - Jun Qian
- Zhenjiang Clinical Research Center of Hematology, Jiangsu, China.,Department of Hematology, Affiliated People's Hospital of Jiangsu University, Jiangsu, China
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25
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Kovaleva OV, Belova TP, Korotkova EA, Kushlinskii DN, Gratchev AN, Petrikova NA, Kudlay DA, Kushlinskii NE. Soluble B7-H3 in Ovarian Cancer and Its Predictive Value. Bull Exp Biol Med 2021; 171:472-474. [PMID: 34542756 DOI: 10.1007/s10517-021-05253-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Indexed: 11/29/2022]
Abstract
The content of the soluble form of protein of the key point of immunity B7-H3 (sB7-H3) in the blood plasma of 75 patients with epithelial ovarian cancer before treatment was measured by ELISA. It is known that B7-H3 belongs to the immunoglobulin superfamily (B7 molecule family) and is involved in the regulation of the immune response mediated by T cells. The sB7-H3 concentration correlated with the clinical and morphological parameters of ovarian cancer. The content of sB7-H3 was higher at the later stages of the disease, in the presence of ascites, and in patients with poorly differentiated ovarian cancer. It was revealed that increased plasma content of sB7-H3 in patients with epithelial ovarian cancer is associated with unfavorable prognosis of the disease. Therefore, sB7-H3 can be used as a prognostic marker in ovarian cancer patients.
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Affiliation(s)
- O V Kovaleva
- N. N. Blokhin National Medical Research Center of Oncology, Ministry of Health of the Russian Federation, Moscow, Russia.
| | - T P Belova
- N. N. Blokhin National Medical Research Center of Oncology, Ministry of Health of the Russian Federation, Moscow, Russia
| | - E A Korotkova
- N. N. Blokhin National Medical Research Center of Oncology, Ministry of Health of the Russian Federation, Moscow, Russia
| | - D N Kushlinskii
- A. F. Tsyb Medical Radiological Research Center - Affiliated Branch of the National Medical Research Radiological Center, Ministry of Health of the Russian Federation, Obninsk, Russia
| | - A N Gratchev
- N. N. Blokhin National Medical Research Center of Oncology, Ministry of Health of the Russian Federation, Moscow, Russia
| | - N A Petrikova
- Ryazan Regional Clinical Oncological Center, Ryazan, Russia
| | - D A Kudlay
- Scientific Center Institute of Immunology, Federal Medical-Biological Agency of Russia, Moscow, Russia
| | - N E Kushlinskii
- N. N. Blokhin National Medical Research Center of Oncology, Ministry of Health of the Russian Federation, Moscow, Russia
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26
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Wang J, Chen X, Xie C, Sun M, Hu C, Zhang Z, Luan L, Zhou J, Zhou J, Zhu X, Ouyang J, Dong X, Li D, Zhang J, Zhao X. MicroRNA miR-29a Inhibits Colon Cancer Progression by Downregulating B7-H3 Expression: Potential Molecular Targets for Colon Cancer Therapy. Mol Biotechnol 2021; 63:849-861. [PMID: 34100183 DOI: 10.1007/s12033-021-00348-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 06/01/2021] [Indexed: 12/11/2022]
Abstract
MiR-29a belongs to one of the subtypes of miRNAs known as non-coding single-stranded RNAs and is preferentially expressed in normal tissues. B7-H3, a member of the B7/CD28 immunoglobulin superfamily, was shown to be overexpressed in several solid malignant tumors, including colon cancer. In addition, it is associated with tumor progression and poor prognosis. We used immunohistochemical and Western blotting to assess B7-H3 protein expression levels in colon cancer and adjacent normal tissues and then compared their relationships with clinicopathological factors. Quantitative real-time reverse-transcription PCR was used to assess B7-H3 and miRNA-29a mRNA expression levels, and then their relationship and clinical significance were evaluated. In addition, colon cancer Caco-2 cells, which constitutively overexpress B7-H3, were transfected with lentivirus particles for miR-29a upregulation. Invasion and migration assays were carried out in vitro along with the establishment of a subcutaneous xenograft model in vivo to determine the role of miRNA-29a in colon cancer progression. The B7-H3 protein showed elevated expression in colon carcinoma and was relevant to TNM staging, lymph node metastasis, and reduced survival. Meanwhile, miR-29a was preferentially expressed in normal colon tissues, while B7-H3 transcript levels had no marked differences between tumor and normal tissue specimens. In vitro, miR-29a upregulation resulted in reduced B7-H3 expression. Furthermore, miR-29a upregulation reduced the invasive and migratory abilities of colon carcinoma cells. In animal models, upregulation of miR-29a slowed down the growth of subcutaneous xenotransplanted tumors and resulted in prolonged survival time. MiR-29a downregulates B7-H3 expression and accordingly inhibits colon cancer progression, invasion, and migration, indicating miR-29a and B7-H3 might represent novel molecular targets for advanced immunotherapy in colon cancer.
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Affiliation(s)
- Jin Wang
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
- Department of General Surgery, Suzhou Dushu Lake Hospital (Dushu Lake Hospital Affiliated to Soochow University), Suzhou, China
- Jiangsu Institute of Clinical Immunology, Soochow University, Suzhou, China
- Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, China
- Jiangsu Key Laboratory of Gastrointestinal Tumor Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Xiaojuan Chen
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Chen Xie
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Mingbing Sun
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Chenrui Hu
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Zhe Zhang
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Lipeng Luan
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Jin Zhou
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Jian Zhou
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Xinguo Zhu
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Jun Ouyang
- Department of Urology Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Xiaoqiang Dong
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Dechun Li
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Jianglei Zhang
- Department of Urology Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China.
| | - Xin Zhao
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China.
- Jiangsu Institute of Clinical Immunology, Soochow University, Suzhou, China.
- Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, China.
- Jiangsu Key Laboratory of Gastrointestinal Tumor Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China.
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Khan M, Arooj S, Wang H. Soluble B7-CD28 Family Inhibitory Immune Checkpoint Proteins and Anti-Cancer Immunotherapy. Front Immunol 2021; 12:651634. [PMID: 34531847 PMCID: PMC8438243 DOI: 10.3389/fimmu.2021.651634] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Accepted: 08/04/2021] [Indexed: 12/12/2022] Open
Abstract
Co-inhibitory B7-CD28 family member proteins negatively regulate T cell responses and are extensively involved in tumor immune evasion. Blockade of classical CTLA-4 (cytotoxic T lymphocyte-associated antigen-4) and PD-1 (programmed cell death protein-1) checkpoint pathways have become the cornerstone of anti-cancer immunotherapy. New inhibitory checkpoint proteins such as B7-H3, B7-H4, and BTLA (B and T lymphocyte attenuator) are being discovered and investigated for their potential in anti-cancer immunotherapy. In addition, soluble forms of these molecules also exist in sera of healthy individuals and elevated levels are found in chronic infections, autoimmune diseases, and cancers. Soluble forms are generated by proteolytic shedding or alternative splicing. Elevated circulating levels of these inhibitory soluble checkpoint molecules in cancer have been correlated with advance stage, metastatic status, and prognosis which underscore their broader involvement in immune regulation. In addition to their potential as biomarker, understanding their mechanism of production, biological activity, and pathological interactions may also pave the way for their clinical use as a therapeutic target. Here we review these aspects of soluble checkpoint molecules and elucidate on their potential for anti-cancer immunotherapy.
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Affiliation(s)
- Muhammad Khan
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei, China
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China
| | - Sumbal Arooj
- Department of Biochemistry, University of Sialkot, Sialkot, Pakistan
| | - Hua Wang
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei, China
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China
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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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Shao L, Yu Q, Xia R, Zhang J, Gu S, Yu D, Zhuang Z. B7-H3 on breast cancer cell MCF7 inhibits IFN-γ release from tumour-infiltrating T cells. Pathol Res Pract 2021; 224:153461. [PMID: 34265738 DOI: 10.1016/j.prp.2021.153461] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 04/28/2021] [Accepted: 05/02/2021] [Indexed: 10/21/2022]
Abstract
B7-H3 is a type I membrane protein that has contradictory co-stimulatory and co-inhibitory effects in adaptive and anti-tumour immunity. B7-H3 is up-regulated in many malignant tumours, including breast cancer. Therefore, we hypothesise that B7-H3, which has an immunosuppressive role, suppresses anti-tumour immunity. The aim of this study was to clarify the role of B7-H3 in the tumor microenvironment in breast cancer, explore the possibility of B7-H3 as a target for clinical immunotherapy, and provide reference for clinical work. We knocked down B7-H3 with siRNA in MCF7 breast cancer cells, which we termed MCF7-B7-H3-KD cells, and the expression of B7-H3 was assessed by flow cytometry. GAPDH (glyceraldehyde-3-phosphate dehydrogenase) knockdown was used as a control (MCF7-Gapdh). MCF7-B7-H3-KD and MCF7-Gapdh cells were co-cultured with peripheral blood mononuclear cells (PBMCs) and CD3+ T cells from healthy donors to assess the effect of B7-H3 loss. PBMCs cultured with MCF7-Gapdh cells showed decreased activation, proliferation, and function of CD8+ T cells, but there was no effect on the proliferation of CD4+ T cells. However, when MCF7-B7-H3-KD cells were co-cultured with PBMCs, the proliferation ability of CD4+ T cells and CD8+ T cells was significantly higher than that observed in MCF7-Gapdh cell co-culture. Additionally, co-culture with MCF7-Gapdh cells decreased the expression of IFN-γ (Interferon-γ). However, after co-culture with MCF7-B7-H3-KD cells, there was an increase in IFN-γ. We further found that this inhibitory effect on IFN-γ was because of decreased mTOR (the mammalian target of rapamycin) phosphorylation in T cells. Treatment of T cells co-cultured with MCF7-B7-H3-KD cells with an mTOR inhibitor blocked the secretion of IFN-γ. B7-H3 on tumour cells inhibits the proliferation of CD4+ and CD8+ T cells and inhibits the release of IFN-γ by decreasing mTOR signalling. A better understanding of these complex immune regulatory mechanisms should facilitate the generation of more powerful and selective tools to manipulate cancer therapy.
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Affiliation(s)
- Lili Shao
- Department of Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, China; Department of Medical Oncology, Affiliated Tumor Hospital of Nantong University, Nantong Tumor Hospital, Nantong, China
| | - Qiongzhu Yu
- Department of Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Rui Xia
- Department of Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - JiaYu Zhang
- Department of Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Siyi Gu
- Department of Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Daojiang Yu
- Department of Plastic Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, China.
| | - Zhixiang Zhuang
- Department of Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, China.
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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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Li ZY, Wang JT, Chen G, Shan ZG, Wang TT, Shen Y, Chen J, Yan ZB, Peng LS, Mao FY, Teng YS, Liu JS, Zhou YY, Zhao YL, Zhuang Y. Expression, regulation and clinical significance of B7-H3 on neutrophils in human gastric cancer. Clin Immunol 2021; 227:108753. [PMID: 33945871 DOI: 10.1016/j.clim.2021.108753] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 04/27/2021] [Accepted: 04/30/2021] [Indexed: 12/15/2022]
Abstract
Neutrophils are conspicuous components of gastric cancer (GC) tumors, increasing with tumor progression and poor patient survival. However, the phenotype, regulation and clinical relevance of neutrophils in human GC are presently unknown. Most intratumoral neutrophils showed an activated CD54+ phenotype and expressed high level B7-H3. Tumor tissue culture supernatants from GC patients induced the expression of CD54 and B7-H3 on neutrophils in time-dependent and dose-dependent manners. Locally enriched CD54+ neutrophils and B7-H3+ neutrophils positively correlated with increased granulocyte-macrophage colony stimulating factor (GM-CSF) detection ex vivo; and in vitro GM-CSF induced the expression of CD54 and B7-H3 on neutrophils in both time-dependent and dose-dependent manners. Furthermore, GC tumor-derived GM-CSF activated neutrophils and induced neutrophil B7-H3 expression via JAK-STAT3 signaling pathway activation. Finally, intratumoral B7-H3+ neutrophils increased with tumor progression and independently predicted reduced overall survival. Collectively, these results suggest B7-H3+ neutrophils to be potential biomarkers in GC.
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Affiliation(s)
- Zheng-Yan Li
- Department of General Surgery and Center of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Jin-Tao Wang
- Department of General Surgery and Center of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Gang Chen
- Department of General Surgery and Center of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Zhi-Guo Shan
- Department of General Surgery and Center of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Ting-Ting Wang
- Chongqing Key Research Laboratory for Drug Metabolism, Department of Pharmacology, Chongqing Medical University, Chongqing, China
| | - Yang Shen
- Department of Oncology, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
| | - Jun Chen
- Department of General Surgery and Center of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Zong-Bao Yan
- Department of General Surgery and Center of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Liu-Sheng Peng
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine, Third Military Medical University, Chongqing, China
| | - Fang-Yuan Mao
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine, Third Military Medical University, Chongqing, China
| | - Yong-Sheng Teng
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine, Third Military Medical University, Chongqing, China
| | - Jin-Shan Liu
- Department of General Surgery, Qijiang Hospital of the First Affiliated Hospital of Chongqing Medical University, Qijiang, Chongqing, China
| | - Yuan-Yuan Zhou
- Department of Gastroenterology, XinQiao Hospital, Third Military Medical University, Chongqing, China.
| | - Yong-Liang Zhao
- Department of General Surgery and Center of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China.
| | - Yuan Zhuang
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine, Third Military Medical University, Chongqing, China; Department of Gastroenterology, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China.
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Cancer Stem Cells Are Possible Key Players in Regulating Anti-Tumor Immune Responses: The Role of Immunomodulating Molecules and MicroRNAs. Cancers (Basel) 2021; 13:cancers13071674. [PMID: 33918136 PMCID: PMC8037840 DOI: 10.3390/cancers13071674] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 03/05/2021] [Accepted: 03/09/2021] [Indexed: 12/14/2022] Open
Abstract
Simple Summary This review provides a critical overview of the state of the art of the characterization of the immunological profile of a rare component of the tumors, denominated cancer stem cells (CSCs) or cancer initiating cells (CICs). These cells are endowed with the ability to form and propagate tumors and resistance to therapies, including the most innovative approaches. These investigations contribute to understanding the mechanisms regulating the interaction of CSCs/CICs with the immune system and identifying novel therapeutic approaches to render these cells visible and susceptible to immune responses. Abstract Cancer cells endowed with stemness properties and representing a rare population of cells within malignant lesions have been isolated from tumors with different histological origins. These cells, denominated as cancer stem cells (CSCs) or cancer initiating cells (CICs), are responsible for tumor initiation, progression and resistance to therapies, including immunotherapy. The dynamic crosstalk of CSCs/CICs with the tumor microenvironment orchestrates their fate and plasticity as well as their immunogenicity. CSCs/CICs, as observed in multiple studies, display either the aberrant expression of immunomodulatory molecules or suboptimal levels of molecules involved in antigen processing and presentation, leading to immune evasion. MicroRNAs (miRNAs) that can regulate either stemness properties or their immunological profile, with in some cases dual functions, can provide insights into these mechanisms and possible interventions to develop novel therapeutic strategies targeting CSCs/CICs and reverting their immunogenicity. In this review, we provide an overview of the immunoregulatory features of CSCs/CICs including miRNA profiles involved in the regulation of the interplay between stemness and immunological properties.
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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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Meng F, Yang M, Chen Y, Chen W, Wang W. miR-34a induces immunosuppression in colorectal carcinoma through modulating a SIRT1/NF-κB/B7-H3/TNF-α axis. Cancer Immunol Immunother 2021; 70:2247-2259. [PMID: 33492448 DOI: 10.1007/s00262-021-02862-2] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Accepted: 01/15/2021] [Indexed: 12/14/2022]
Abstract
Although a number of studies have revealed the important roles of miR-34a in cancer, the regulatory roles of miR-34a in cancer immune response remain largely unknown. Our present study demonstrated a mechanism underlying miR-34a-mediated cancer immune evasion via a SIRT1/NF-κB/B7-H3/TNF-α axis. miR-34a upregulated B7-H3, an important immune checkpoint molecule, through direct inhibition of SIRT1 and consequent acetylation of NF-κB subunit p65 (a-p65), which promoted B7-H3 transcription by direct binding to its promoter. The elevated B7-H3 induced production of pro-inflammatory cytokines including TNF-α. This was further confirmed in the colon of Mir34a-deficient mice, where Sirt1 expression was boosted, and the expressions of a-p65, B7h3, and Tnf were repressed. Consequently, the in vivo inhibitory activity of miR-34a on colorectal cancer (CRC) was eradicated by the reinforced B7-H3 and TNF-α. In conclusion, our study uncovered an etiological mechanism underlying miR-34a-mediated CRC immune evasion through inhibition of SIRT1 and promotion of NF-κB/B7-H3/TNF-α axis.
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Affiliation(s)
- Fanyi Meng
- Center for Drug Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences, Soochow University, Yunxuan Building #1339, Wenjing Road, Suzhou Industrial Park, Suzhou, 215123, China
| | - Man Yang
- Center for Drug Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences, Soochow University, Yunxuan Building #1339, Wenjing Road, Suzhou Industrial Park, Suzhou, 215123, China
| | - Yinshuang Chen
- Center for Drug Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences, Soochow University, Yunxuan Building #1339, Wenjing Road, Suzhou Industrial Park, Suzhou, 215123, China
| | - Weichang Chen
- Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, 215006, China. .,Jiangsu Key Laboratory of Gastrointestinal Tumor Immunology, Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Shizhi Street 188, Suzhou, 215006, China.
| | - Weipeng Wang
- Center for Drug Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences, Soochow University, Yunxuan Building #1339, Wenjing Road, Suzhou Industrial Park, Suzhou, 215123, China.
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Abstract
PURPOSE OF REVIEW Immunotherapy has shown an unprecedented response in treatment of tumors. However, challenges such as lack of cytotoxic lymphocytes to mount an immune response or development of resistance to therapy can limit efficacy. Here, we discuss alternative checkpoints that can be targeted to improve cytotoxic lymphocyte function while harnessing other components of the immune system. RECENT FINDINGS Blockade of alternative checkpoints has improved anti-tumor immunity in mouse models and is being tested clinically with encouraging findings. In addition to modulating T cell function directly, alternative checkpoints can also regulate activity of myeloid cells and regulatory T cells to affect anti-tumor response. Combination of immune checkpoint inhibitors can improve treatment of tumors by activating multiple arms of the immune system.
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Affiliation(s)
- Ayush Pant
- Department of Neurosurgery, Neurosurgery Oncology, Radiation Oncology, Otolaryngology, and Institute of NanoBiotechnology, Brain Tumor Immunotherapy Program, Metastatic Brain Tumor Center, The Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Phipps 123, Baltimore, MD, 21287, USA
| | - Ravi Medikonda
- Department of Neurosurgery, Neurosurgery Oncology, Radiation Oncology, Otolaryngology, and Institute of NanoBiotechnology, Brain Tumor Immunotherapy Program, Metastatic Brain Tumor Center, The Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Phipps 123, Baltimore, MD, 21287, USA
| | - Michael Lim
- Department of Neurosurgery, Neurosurgery Oncology, Radiation Oncology, Otolaryngology, and Institute of NanoBiotechnology, Brain Tumor Immunotherapy Program, Metastatic Brain Tumor Center, The Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Phipps 123, Baltimore, MD, 21287, USA.
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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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B7-H3 expression in upper tract urothelial carcinoma associates with adverse clinicopathological features and poor survival. Pathol Res Pract 2020; 216:153219. [PMID: 33049447 DOI: 10.1016/j.prp.2020.153219] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 09/10/2020] [Accepted: 09/14/2020] [Indexed: 12/17/2022]
Abstract
B7-H3, a member of the B7 superfamily, is an immune checkpoint molecule. An association between B7-H3 expression and poor survival has been reported in many types of cancer. However, its prognostic value in patients with upper tract urothelial carcinoma (UTUC) has not yet been reported. The aim of this study was to examine the clinical significance of tumor B7-H3 expression in UTUC. B7-H3 positivity was observed in 36 of 271 cases (13 %) by immunohistochemistry and was significantly associated with several adverse clinicopathological features such as tumor grade, tumor stage, and lymph node metastasis. In addition, B7-H3 positivity was significantly associated with shorter metastasis-free survival and cancer-specific survival. We also found that B7-H3/programmed cell death ligand-1 (PD-L1) co-positivity was significantly associated with worse prognosis. These results suggest the utility of B7-H3 positivity and B7-H3/PD-L1 co-positivity as novel prognostic biomarkers in UTUC, and the potential usefulness of B7-H3 targeted therapy for patients with UTUC, the effect of which may be enhanced by combination with programmed cell death-1 /PD-L1 blockade.
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38
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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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39
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Terry RL, Meyran D, Ziegler DS, Haber M, Ekert PG, Trapani JA, Neeson PJ. Immune profiling of pediatric solid tumors. J Clin Invest 2020; 130:3391-3402. [PMID: 32538896 PMCID: PMC7324195 DOI: 10.1172/jci137181] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Pediatric cancers, particularly high-risk solid tumors, urgently need effective and specific therapies. Their outlook has not appreciably improved in decades. Immunotherapies such as immune checkpoint inhibitors offer much promise, but most are only approved for use in adults. Though several hundred clinical trials have tested immune-based approaches in childhood cancers, few have been guided by biomarkers or clinical-grade assays developed to predict patient response and, ultimately, to help select those most likely to benefit. There is extensive evidence in adults to show that immune profiling has substantial predictive value, but few studies focus on childhood tumors, because of the relatively small disease population and restricted use of immune-based therapies. For instance, only one published study has retrospectively examined the immune profiles of pediatric brain tumors after immunotherapy. Furthermore, application and integration of advanced multiplex techniques has been extremely limited. Here, we review the current status of immune profiling of pediatric solid tumors, with emphasis on tumor types that represent enormous unmet clinical need, primarily in the context of immune checkpoint inhibitor therapy. Translating optimized and informative immune profiling into standard practice and access to personalized combination therapy will be critical if childhood cancers are to be treated effectively and affordably.
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Affiliation(s)
- Rachael L. Terry
- Children’s Cancer Institute, Randwick, New South Wales, Australia
| | - Deborah Meyran
- Cancer Immunology Program, Peter MacCallum Cancer Center, Melbourne, Victoria, Australia
- Université de Paris, Inserm, U976 HIPI Unit, Institut de Recherche Saint-Louis, Paris, France
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia
| | - David S. Ziegler
- Children’s Cancer Institute, Randwick, New South Wales, Australia
- Kids Cancer Center, Sydney Children’s Hospital, Randwick, New South Wales, Australia
| | - Michelle Haber
- Children’s Cancer Institute, Randwick, New South Wales, Australia
| | - Paul G. Ekert
- Children’s Cancer Institute, Randwick, New South Wales, Australia
- Cancer Immunology Program, Peter MacCallum Cancer Center, Melbourne, Victoria, Australia
| | - Joseph A. Trapani
- Cancer Immunology Program, Peter MacCallum Cancer Center, Melbourne, Victoria, Australia
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia
| | - Paul J. Neeson
- Cancer Immunology Program, Peter MacCallum Cancer Center, Melbourne, Victoria, Australia
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia
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40
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Cao D, Chen MK, Zhang QF, Zhou YF, Zhang MY, Mai SJ, Zhang YJ, Chen MS, Li XX, Wang HY. Identification of immunological subtypes of hepatocellular carcinoma with expression profiling of immune-modulating genes. Aging (Albany NY) 2020; 12:12187-12205. [PMID: 32544882 PMCID: PMC7343492 DOI: 10.18632/aging.103395] [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: 01/09/2020] [Accepted: 05/20/2020] [Indexed: 12/24/2022]
Abstract
Recent studies demonstrate that immune checkpoint inhibitor (ICI) therapy has achieved success in many types of advanced cancers including advanced hepatocellular carcinoma (HCC). However, ICI therapy is beneficial in only some HCC patients, suggesting that immune-responses are highly variable in HCCs. Therefore, understanding the immune status in HCC microenvironment will facilitate ICI immunotherapy and guide patient selection for the therapy. In this study, we first analyzed the expression profile of immune-modulating genes and their relationship with survival of HCC patients using the data downloaded from The Cancer Genome Atlas - Liver Hepatocellular Carcinoma (TCGA-LIHC) database, and found that the higher expressions of CD276 (B7-H3) and CD47 were significantly associated with poor survival. Then we identified 4 immune subtypes of HCCs with different survivals by using the combination expression of B7-H3 (or CD47) and CD8. Patients with B7-H3low/CD8high or CD47low/CD8high have the best survival while ones with B7-H3high/CD8low or CD47high/CD8low have the worst survival. The 4 immune subtypes were validated in another 72 HCC patients obtained from South China. In conclusion, our findings suggest that HCC patient prognosis is associated with immunophenotypes by T cell infiltration (CD8 expression) and the expression of the adaptive immune resistance gene (B7-H3 or CD47), and this immune classification system will facilitate HCC patient selection for ICI immunotherapy.
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Affiliation(s)
- Di Cao
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Meng-Ke Chen
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Qing-Feng Zhang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Yu-Feng Zhou
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Mei-Yin Zhang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Shi-Juan Mai
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Yao-Jun Zhang
- Department of Hepatobiliary Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Min-Shan Chen
- Department of Hepatobiliary Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Xiao-Xing Li
- Precision Medicine Institute, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Hui-Yun Wang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
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41
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Wang C, Feng H, Cheng X, Liu K, Cai D, Zhao R. Potential Therapeutic Targets of B7 Family in Colorectal Cancer. Front Immunol 2020; 11:681. [PMID: 32477326 PMCID: PMC7232583 DOI: 10.3389/fimmu.2020.00681] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Accepted: 03/26/2020] [Indexed: 12/14/2022] Open
Abstract
Programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) pathway blockade has impressively benefited cancer patients with a wide spectrum of tumors. However, its efficacy in colorectal cancer (CRC) is modest, and only a small subset of patients benefits from approved checkpoint inhibitors. Newer checkpoints that target additional immunomodulatory pathways are becoming necessary to activate durable antitumor immune responses in patients with CRC. In this review, we evaluated the mRNA expression of all 10 reported B7 family members in human CRC by retrieving and analyzing the TCGA database and reviewed the current understanding of the top three B7 family checkpoint molecules (B7-H3, VISTA, and HHLA2) with the highest mRNA expression, introducing them as putative therapeutic targets in CRC.
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Affiliation(s)
- Changgang Wang
- Department of General Surgery, Ruijin Hospital North, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Haoran Feng
- Department of General Surgery, Ruijin Hospital North, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xi Cheng
- Department of General Surgery, Ruijin Hospital North, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Kun Liu
- Department of General Surgery, Ruijin Hospital North, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Dongli Cai
- Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China
| | - Ren Zhao
- Department of General Surgery, Ruijin Hospital North, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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42
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Li F, Chen H, Wang D. Silencing of CD276 suppresses lung cancer progression by regulating integrin signaling. J Thorac Dis 2020; 12:2137-2145. [PMID: 32642118 PMCID: PMC7330387 DOI: 10.21037/jtd.2020.04.41] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Background Non-small cell lung cancer (NSCLC) is one of the cancers with the highest morbidity and mortality among the world. Studies have shown that the invasion and metastasis of tumor are biological characteristics of lung cancer, and also the main cause of treatment failure and patient death. In-depth study of lung cancer invasion related genes will help to explore the etiology of lung cancer, molecular typing and individualized treatment of lung cancer. Studies have shown that CD276 molecules are closely related to the prognosis of tumors, but the exact mechanism remains to be unclear. Methods We used the UALCAN and KM-plotter databases to investigate the expression of CD276 in human NSCLC and adjacent normal tissues, and its correlation with clinicopathology. In addition, we analyzed the function of CD276 in NSCLC cell by suppressing the expression of CD276 in A549 and H460 cells. Results In this study, we found that CD276 expression was significantly up-regulated in NSCLC tissues, and its expression was positively correlated with tumor stage in NSCLC. Silencing in CD276 inhibited cell invasion and migration by reducing integrin-associated protein expression. Conclusions Our results indicate functional role of CD276 in the progression of NSCLC.
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Affiliation(s)
- Fang Li
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Hengchi Chen
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Dali Wang
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
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43
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Lu H, Shi T, Wang M, Li X, Gu Y, Zhang X, Zhang G, Chen W. B7-H3 inhibits the IFN-γ-dependent cytotoxicity of Vγ9Vδ2 T cells against colon cancer cells. Oncoimmunology 2020; 9:1748991. [PMID: 32363121 PMCID: PMC7185217 DOI: 10.1080/2162402x.2020.1748991] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Revised: 02/12/2020] [Accepted: 03/22/2020] [Indexed: 12/19/2022] Open
Abstract
The immunoregulatory protein B7-H3, a member of the B7 family, has been confirmed to be highly expressed in colon cancer. However, the exact influence of B7-H3 on the features and antitumor ability of γδT cells in colon cancer remains unknown. In the present study, we investigated that the proportions of B7-H3+ γδT cells were distinctly increased in the peripheral blood and tumor tissues of colon cancer patients. B7-H3 blockade or knockdown promoted proliferation, inhibited cell apoptosis and induced the expression of activation markers (CD25 and CD69) on Vδ2 T cells. In contrast, treatment with the B7-H3 agonist 4H7 had the opposite effect. Furthermore, B7-H3 suppressed IFN-γ expression by inhibiting T-bet in Vδ2 T cells. Moreover, B7-H3 mediated the inhibition of Vδ2 T cell cytotoxicity via the downregulation of IFN-γ and perforin/granzyme B expression. More importantly, blocking the B7-H3 function significantly enhanced the cytotoxicity of Vδ2 T cells against colon cancer cells in vivo. Therefore, the inhibition or blockade of B7-H3 is a potential immunotherapeutic approach for colon cancer.
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Affiliation(s)
- Huimin Lu
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China.,Jiangsu Institute of Clinical Immunology, the First Affiliated Hospital of Soochow University, Suzhou, China.,Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, China
| | - Tongguo Shi
- Jiangsu Institute of Clinical Immunology, the First Affiliated Hospital of Soochow University, Suzhou, China.,Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, China.,Jiangsu Key Laboratory of Gastrointestinal Tumor Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | | | - Xiaomi Li
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Yanzheng Gu
- Jiangsu Institute of Clinical Immunology, the First Affiliated Hospital of Soochow University, Suzhou, China.,Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, China.,Jiangsu Key Laboratory of Gastrointestinal Tumor Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Xueguang Zhang
- Jiangsu Institute of Clinical Immunology, the First Affiliated Hospital of Soochow University, Suzhou, China.,Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, China.,Jiangsu Key Laboratory of Gastrointestinal Tumor Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Guangbo Zhang
- Jiangsu Institute of Clinical Immunology, the First Affiliated Hospital of Soochow University, Suzhou, China.,Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, China.,Jiangsu Key Laboratory of Gastrointestinal Tumor Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Weichang Chen
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China.,Jiangsu Institute of Clinical Immunology, the First Affiliated Hospital of Soochow University, Suzhou, China.,Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, China.,Jiangsu Key Laboratory of Gastrointestinal Tumor Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China
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44
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Liu L, He H, Xu D, Feng Y, Zhou H, Shi L, Gu Y, Wang J, Zhu Y. Association between interleukin-36γ and tumor progression in non-small cell lung cancer. Oncol Lett 2020; 19:2457-2465. [PMID: 32194745 PMCID: PMC7039103 DOI: 10.3892/ol.2020.11319] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Accepted: 12/13/2019] [Indexed: 01/21/2023] Open
Abstract
Immunotherapy is effective in improving the survival and prognosis of patients with non-small cell lung cancer (NSCLC), and identifying effective immunomarkers is important for immunotherapy. Interleukin (IL)-36γ is a novel immunomarker that has an important function in the antitumor immune response. The present study investigated the association between IL-36γ and NSCLC to provide novel insight into immunotherapy for patients with NSCLC. Tissue microarrays of lung adenocarcinoma and squamous cell carcinoma were purchased for immunohistochemical analysis of IL-36γ expression levels and clinical parameters. In addition, fresh clinical NSCLC and adjacent normal tissue samples were collected to analyze IL-36γ mRNA expression levels using quantitative PCR. IL-36γ protein was primarily located in the cytoplasm, with a small quantity in the nucleus, and IL-36γ mRNA and protein expression levels in lung cancer tissues were significantly higher compared with those in adjacent normal tissues. Elevated IL-36γ protein expression levels were significantly associated with a higher tumor grade of lung adenocarcinoma; however, IL-36γ mRNA expression levels were inversely associated with the clinical Tumor-Node-Metastasis stage in patients with lung squamous cell carcinoma. In addition, patients with adenocarcinoma with high IL-36γ protein expression levels tended to longer post-operative survival times. These findings indicate that IL-36γ may have potential as an immunomarker for prediction of tumor progression and survival in patients with NSCLC.
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Affiliation(s)
- Lin Liu
- Department of Immunology, School of Biology and Basic Medical Sciences, Soochow University, Suzhou, Jiangsu 215123, P.R. China.,Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, Jiangsu 215025, P.R. China
| | - Honghong He
- Department of Immunology, School of Biology and Basic Medical Sciences, Soochow University, Suzhou, Jiangsu 215123, P.R. China.,Suzhou Blood Center, Soochow University, Suzhou, Jiangsu 215006, P.R. China.,Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Dan Xu
- Department of Immunology, School of Biology and Basic Medical Sciences, Soochow University, Suzhou, Jiangsu 215123, P.R. China.,Clinical Laboratory, Yancheng Maternal and Child Health Hospital, Yancheng, Jiangsu 224002, P.R. China
| | - Yuehua Feng
- Comprehensive Laboratory, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, P.R. China
| | - Huijun Zhou
- Department of Immunology, School of Biology and Basic Medical Sciences, Soochow University, Suzhou, Jiangsu 215123, P.R. China
| | - Liyan Shi
- Department of Immunology, School of Biology and Basic Medical Sciences, Soochow University, Suzhou, Jiangsu 215123, P.R. China
| | - Yanzheng Gu
- Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, Jiangsu 215006, P.R. China.,Clinical Immunology Institute, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Jian Wang
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, Jiangsu 215025, P.R. China
| | - Yibei Zhu
- Department of Immunology, School of Biology and Basic Medical Sciences, Soochow University, Suzhou, Jiangsu 215123, P.R. China.,Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, Jiangsu 215006, P.R. China
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45
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Expression and Clinical Significance of Immune Checkpoint Regulator B7-H3 (CD276) in Human Meningioma. World Neurosurg 2020; 135:e12-e18. [DOI: 10.1016/j.wneu.2019.10.044] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Revised: 10/06/2019] [Accepted: 10/08/2019] [Indexed: 11/17/2022]
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46
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Ge Y, Chen W, Zhang X, Wang H, Cui J, Liu Y, Ju S, Tian X, Ju S. Nuclear-localized costimulatory molecule 4-1BBL promotes colon cancer cell proliferation and migration by regulating nuclear Gsk3β, and is linked to the poor outcomes associated with colon cancer. Cell Cycle 2020; 19:577-591. [PMID: 31992123 DOI: 10.1080/15384101.2020.1719308] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
Anti-tumor immune response and the prognosis of tumor are the results of competition between stimulatory and inhibitory checkpoints. Except for upregulating inhibitory checkpoints, lowering some immune accelerating molecules to convert an immunostimulatory microenvironment into an immunodormant one through "decelerating the accelerator" might be another effective immune escape pattern. 4-1BBL is a classical transmembrane costimulatory molecule involving in antitumor immune responses. In contrast, we demonstrated that 4-1BBL is predominantly localized in the nuclei of cancer cells in colon cancer specimens and is positively correlated with tumor size, lymph node metastasis, and a lower survival ratio. Furthermore, the nuclear localization of 4-1BBL was also ascertained in vitro. 4-1BBL knockout (KO) arrests the proliferation and impaired the migration and invasion ability of colon cancer cells in vitro and retarded tumor growth in vivo. 4-1BBL KO increased the accumulation of Gsk3β in the nuclei of colon cancer cells and consequently decreased the expression of Wnt pathway target genes and thus alter tumor biological behavior. We hypothesized that unlike membrane-expressed 4-1BBL, which stimulates the 4-1BB signaling of antitumor cytotoxic T cells, the nuclear-localized 4-1BBL could facilitate the malignant behavior of colon cancer cells by circumventing antitumor signaling and driving some key oncotropic signal pathway in the nucleus. Nuclear-localized 4-1BBL might be an indicator of colon cancer malignancy and serve as a promising target of immunotherapy.
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Affiliation(s)
- Yan Ge
- Department of Immunology, School of Biology and Basic Medical Sciences, Medical College, Soochow University, Suzhou, Jiangsu Province, China
| | - Wei Chen
- Department of General Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
| | - Xueguang Zhang
- Department of Immunology, School of Biology and Basic Medical Sciences, Medical College, Soochow University, Suzhou, Jiangsu Province, China
| | - Haiyan Wang
- Department of Immunology, School of Biology and Basic Medical Sciences, Medical College, Soochow University, Suzhou, Jiangsu Province, China
| | - Juanjuan Cui
- Department of Immunology, School of Biology and Basic Medical Sciences, Medical College, Soochow University, Suzhou, Jiangsu Province, China
| | - Yue Liu
- Department of Immunology, School of Biology and Basic Medical Sciences, Medical College, Soochow University, Suzhou, Jiangsu Province, China
| | - Songwen Ju
- Central Laboratory, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu Province, China
| | - Xinxin Tian
- Department of Immunology, School of Biology and Basic Medical Sciences, Medical College, Soochow University, Suzhou, Jiangsu Province, China.,Departmemt of Medical Care for Cadres, Nanjing Municipal Government Hospital, Nanjing, Jiangsu Province, China
| | - Songguang Ju
- Department of Immunology, School of Biology and Basic Medical Sciences, Medical College, Soochow University, Suzhou, Jiangsu Province, China
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Wang R, Ma Y, Zhan S, Zhang G, Cao L, Zhang X, Shi T, Chen W. B7-H3 promotes colorectal cancer angiogenesis through activating the NF-κB pathway to induce VEGFA expression. Cell Death Dis 2020; 11:55. [PMID: 31974361 PMCID: PMC6978425 DOI: 10.1038/s41419-020-2252-3] [Citation(s) in RCA: 145] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2019] [Revised: 01/09/2020] [Accepted: 01/10/2020] [Indexed: 02/07/2023]
Abstract
Tumor angiogenesis is a hallmark of cancer and is involved in the tumorigenesis of solid tumors. B7-H3, an immune checkpoint molecule, plays critical roles in proliferation, metastasis and tumorigenesis in diverse tumors; however, little is known about the biological functions and molecular mechanism underlying B7-H3 in regulating colorectal cancer (CRC) angiogenesis. In this study, we first demonstrated that the expression of B7-H3 was significantly upregulated and was positively associated with platelet endothelial cell adhesion molecule-1 (CD31) level in tissue samples from patients with CRC. In addition, a series of in vitro and in vivo experiments showed that conditioned medium from B7-H3 knockdown CRC cells significantly inhibited the migration, invasion, and tube formation of human umbilical vein endothelial cells (HUVECs), whereas overexpression of B7-H3 had the opposite effect. Furthermore, B7-H3 promoted tumor angiogenesis by upregulating VEGFA expression. Recombinant VEGFA abolished the inhibitory effects of conditioned medium from shB7-H3 CRC cells on HUVEC angiogenesis, while VEGFA siRNA or a VEGFA-neutralizing antibody reversed the effects of conditioned medium from B7-H3-overexpressing CRC cells on HUVEC angiogenesis. Moreover, we verified that B7-H3 upregulated VEGFA expression and angiogenesis by activating the NF-κB pathway. Collectively, our findings identify the B7-H3/NF-κB/VEGFA axis in promoting CRC angiogenesis, which serves as a promising approach for CRC treatment.
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Affiliation(s)
- Ruoqin Wang
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, 188 Shizi Road, Suzhou, China.,Jiangsu Key Laboratory of Clinical Immunology, Soochow University, 708 Renmin Road, Suzhou, China
| | - Yanchao Ma
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, 188 Shizi Road, Suzhou, China
| | - Shenghua Zhan
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, 708 Renmin Road, Suzhou, China
| | - Guangbo Zhang
- Jiangsu Key Laboratory of Clinical Immunology, Soochow University, 708 Renmin Road, Suzhou, China.,Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, 708 Renmin Road, Suzhou, China
| | - Lei Cao
- Jiangsu Key Laboratory of Gastrointestinal tumor Immunology, The First Affiliated Hospital of Soochow University, 708 Renmin Road, Suzhou, China
| | - Xueguang Zhang
- Jiangsu Key Laboratory of Clinical Immunology, Soochow University, 708 Renmin Road, Suzhou, China.,Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, 708 Renmin Road, Suzhou, China.,Jiangsu Key Laboratory of Gastrointestinal tumor Immunology, The First Affiliated Hospital of Soochow University, 708 Renmin Road, Suzhou, China
| | - Tongguo Shi
- Jiangsu Key Laboratory of Clinical Immunology, Soochow University, 708 Renmin Road, Suzhou, China. .,Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, 708 Renmin Road, Suzhou, China.
| | - Weichang Chen
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, 188 Shizi Road, Suzhou, China.
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Clinicopathological and Prognostic Characteristics of CD276 (B7-H3) Expression in Adrenocortical Carcinoma. DISEASE MARKERS 2020; 2020:5354825. [PMID: 31998416 PMCID: PMC6977319 DOI: 10.1155/2020/5354825] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Revised: 11/13/2019] [Accepted: 11/29/2019] [Indexed: 02/05/2023]
Abstract
Background Adrenocortical carcinoma (ACC) is a rare malignant endocrine tumor with a high tumor recurrence rate and poor postoperative survival. Recent studies suggest that CD276- (B7-H3) targeted therapy represents a promising therapeutic option for solid tumors. However, little is known about the expression status of CD276 or its association with progression and prognosis of ACC. Methods Clinical data were retrospectively analyzed from patients who underwent resection of ACC at our institution (n = 48). Archived, formalin-fixed, and paraffin-embedded samples were collected for immunohistochemical analysis, and the correlation between CD276 expression and clinicopathological parameters was evaluated. Kaplan-Meier and univariate/multivariate Cox regression methods were implemented to identify any prognostic effects. Data from The Cancer Genome Atlas (TCGA) ACC cohort (n = 48). Archived, formalin-fixed, and paraffin-embedded samples were collected for immunohistochemical analysis, and the correlation between CD276 expression and clinicopathological parameters was evaluated. Kaplan-Meier and univariate/multivariate Cox regression methods were implemented to identify any prognostic effects. Data from The Cancer Genome Atlas (TCGA) ACC cohort (. Results Positive expression of CD276 was detected on the cell membrane and in the cytoplasm of cancer cells or tumor-associated vascular cells in 91.67% (44/48) of ACCs. Vascular expression of CD276 was associated with local aggression (higher T stage, P = 0.029) and advanced ENSAT stage (P = 0.029) and advanced ENSAT stage (P = 0.029) and advanced ENSAT stage (P = 0.029) and advanced ENSAT stage (P = 0.029) and advanced ENSAT stage (P = 0.029) and advanced ENSAT stage (. Conclusion These findings highlight the immune checkpoint factor CD276 as an independent prognostic factor and a potential therapeutic target in ACC.
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Zhan S, Liu Z, Zhang M, Guo T, Quan Q, Huang L, Guo L, Cao L, Zhang X. Overexpression of B7-H3 in α-SMA-Positive Fibroblasts Is Associated With Cancer Progression and Survival in Gastric Adenocarcinomas. Front Oncol 2020; 9:1466. [PMID: 31998637 PMCID: PMC6966326 DOI: 10.3389/fonc.2019.01466] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Accepted: 12/06/2019] [Indexed: 12/14/2022] Open
Abstract
Background: B7-H3 promotes tumor immune escape and is highly expressed in tumor tissues. Stromal cells in tumors, including fibroblasts, play an important role in this process; however, the role of B7-H3 in tumor fibroblasts has not been fully clarified. Methods: We examined B7-H3, CD31, and alpha-smooth muscle actin (α-SMA) protein expression in 268 gastric adenocarcinomas (GACs) by immunohistochemistry. The coexpression of B7-H3 with CD31 or α-SMA was examined using immunofluorescence double staining. Cytokine expression from fibroblasts treated with B7-H3 small interfering RNA (siRNA) was analyzed by a Quantitative reverse transcription-polymerase chain reaction (qPCR) and Enzyme-linked immunosorbent assay (ELISA). The transwell tests were conducted to assess the migration and invasion ability of fibroblasts. The overall survival was analyzed by a Kaplan-Meier analysis. Associations between categorical variables were assessed using the Pearson's Chi-square test or Fisher's exact test. Results: GAC patients with B7-H3 expression showed significantly poorer survival (P = 0.012). The overall survival of the group with high B7-H3 expression was significantly worse than the group with low B7-H3 expression in both tumor cells and in stromal cells (P = 0.007 and P = 0.048, respectively). B7-H3 expression correlated with many clinicopathological data, including tumor stage, tumor depth, lymph node involvement, and survival. Immunofluorescence staining showed that B7-H3 was expressed in tumor cells and α-SMA-positive fibroblasts. Remarkably, high expression of α-SMA was associated with a poor prognosis (P = 0.007), and the prognoses of patients with high stromal expression of B7-H3 and α-SMA were significantly worse than that of other combination types (P = 0.001). Additionally, the absence of B7-H3 led to decreased secretion of cytokines, such as interleukin (IL)-6 and vascular endothelial growth factor (VEGF), as well as a decline in migration and invasion ability in cancer-associated fibroblasts (CAFs). Conclusions: Patients with high B7-H3 expression either in tumor cells or in stromal cells had significantly poorer overall survival. Stromal B7-H3 expression was mostly detected in α-SMA-positive CAFs. GAC patients with both stromal B7-H3-high and α-SMA-high expression had significantly poorer overall survival, suggesting that stromal B7-H3 and α-SMA expression status can serve as an indicator of poor prognosis for GAC patients.
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Affiliation(s)
- Shenghua Zhan
- Department of Pathology, Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Zhiju Liu
- Department of Pathology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Min Zhang
- Department of Pathology, Children's Hospital of Soochow University, Suzhou, China
| | - Tianwei Guo
- Department of Pathology, Changshu Hospital of Affiliated to Nanjing University of Chinese Medicine, Changshu, China
| | - Qiuying Quan
- Department of Pathology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Lili Huang
- Department of Clinical Laboratory, Children's Hospital of Soochow University, Suzhou, China
| | - Lingchuan Guo
- Department of Pathology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Lei Cao
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Xueguang Zhang
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China.,Jiangsu Key Laboratory of Gastrointestinal Tumor Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China.,Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, China
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Kasten BB, Ferrone S, Zinn KR, Buchsbaum DJ. B7-H3-targeted Radioimmunotherapy of Human Cancer. Curr Med Chem 2020; 27:4016-4038. [PMID: 30836909 PMCID: PMC8668195 DOI: 10.2174/0929867326666190228120908] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Revised: 01/28/2019] [Accepted: 01/28/2019] [Indexed: 12/21/2022]
Abstract
BACKGROUND Targeted Radioimmunotherapy (RIT) is an attractive approach to selectively localize therapeutic radionuclides to malignant cells within primary and metastatic tumors while sparing normal tissues from the effects of radiation. Many human malignancies express B7-H3 on the tumor cell surface, while expression on the majority of normal tissues is limited, presenting B7-H3 as a candidate target for RIT. This review provides an overview of the general principles of targeted RIT and discusses publications that have used radiolabeled B7-H3-targeted antibodies for RIT of cancer in preclinical or clinical studies. METHODS Databases including PubMed, Scopus, and Google Scholar were searched for publications through June 2018 using a combination of terms including "B7-H3", "radioimmunotherapy", "targeted", "radiotherapy", and "cancer". After screening search results for relevancy, ten publications were included for discussion. RESULTS B7-H3-targeted RIT studies to date range from antibody development and assessment of novel Radioimmunoconjugates (RICs) in animal models of human cancer to phase II/III trials in humans. The majority of clinical studies have used B7-H3-targeted RICs for intra- compartment RIT of central nervous system malignancies. The results of these studies have indicated high tolerability and favorable efficacy outcomes, supporting further assessment of B7-H3-targeted RIT in larger trials. Preclinical B7-H3-targeted RIT studies have also shown encouraging therapeutic outcomes in a variety of solid malignancies. CONCLUSION B7-H3-targeted RIT studies over the last 15 years have demonstrated feasibility for clinical development and support future assessment in a broader array of human malignancies. Future directions worthy of exploration include strategies that combine B7-H3- targeted RIT with chemotherapy or immunotherapy.
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Affiliation(s)
- Benjamin B. Kasten
- Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, Alabama, U.S.A
| | - Soldano Ferrone
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, U.S.A
| | - Kurt R. Zinn
- Institute for Quantitative Health Science and Engineering, Department of Radiology, Michigan State University, East Lansing, Michigan, U.S.A
| | - Donald J. Buchsbaum
- Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, Alabama, U.S.A
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