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1
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Stec NE, Barker FG, Brastianos PK. Targeted treatment for craniopharyngioma. J Neurooncol 2025; 172:503-513. [PMID: 39951179 DOI: 10.1007/s11060-025-04942-0] [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: 10/22/2024] [Accepted: 01/13/2025] [Indexed: 04/04/2025]
Abstract
INTRODUCTION Craniopharyngioma is a rare solid-cystic tumor of the hypothalamopituitary region. Two distinct craniopharyngioma types (formerly subtypes), adamantinomatous and papillary, have been described. These tumors often manifest with neuroendocrine dysfunction, vision problems, hydrocephalus, and cognitive changes. Despite efforts to spare vital brain structures, conventional treatments such as surgery and radiation can exacerbate preceding deficits and contribute to permanent neurologic impairment. Recent studies have identified BRAF-V600E mutations in nearly all papillary craniopharyngiomas (PCP), and CTNNB1/Wnt pathway alterations in adamantinomatous craniopharyngiomas (ACP). These discoveries have advanced our understanding of craniopharyngioma pathogenesis and have opened opportunities for targeted biological treatments. PURPOSE The primary objective of this article is to review the current landscape of targeted treatments in papillary and adamantinomatous craniopharyngioma. RESULTS Treatment of PCP with BRAF/MEK inhibition has demonstrated durable tumor response in the adjuvant and neoadjuvant settings in multiple case studies and one phase II clinical trial. Although treatment advances are more limited for ACP, CTNNB1/Wnt pathway inhibitors showed promising results in pre-clinical studies and are under continued investigation. CONCLUSION The efficacy of BRAF/MEK inhibition in PCP supports the use of targeted therapy in patients with newly diagnosed PCP. The optimal targeted treatment combinations and their timing, duration, long-term effects, and sequencing with traditional therapeutic modalities have not been established and warrant further study. Targeted therapies represent a significant advancement in the field of oncology, and craniopharyngiomas are viable candidates for these approaches pending further research.
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Affiliation(s)
- Natalie E Stec
- Divisions of Neuro-Oncology and Hematology/Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, 55 Fruit Street, Boston, MA, 02114, USA
| | - Fred G Barker
- Department of Neurosurgery, Massachusetts General Hospital Cancer Center, Harvard Medical School, 55 Fruit Street, Boston, MA, 02114, USA
| | - Priscilla K Brastianos
- Divisions of Neuro-Oncology and Hematology/Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, 55 Fruit Street, Boston, MA, 02114, USA.
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Luo Y, Yuan Y, Liu D, Peng H, Shen L, Chen Y. Targeting novel immune checkpoints in the B7-H family: advancing cancer immunotherapy from bench to bedside. Trends Cancer 2025:S2405-8033(25)00055-X. [PMID: 40113530 DOI: 10.1016/j.trecan.2025.02.007] [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: 12/04/2024] [Revised: 02/20/2025] [Accepted: 02/24/2025] [Indexed: 03/22/2025]
Abstract
The B7-H family of immune checkpoint molecules is a crucial component of the immune regulatory network for tumors, offering new opportunities to modulate the tumor microenvironment (TME). The B7-H family - which includes B7-H2 (inducible T cell costimulatory ligand, ICOSL), B7-H3, B7-H4, B7-H5 (V-domain immunoglobulin suppressor of T cell activation, VISTA), B7-H6, and B7-H7 (HHLA2) - is known for its diverse roles in regulating innate and adaptive immunity. These molecules can exhibit co-stimulatory or co-inhibitory effects on T cells, influencing processes such as T cell activation, differentiation, and effector functions, and they are involved in the recruitment and polarization of various immune cells. This review explores the structural characteristics, receptor-ligand interactions, and signaling pathways associated with each B7-H family member. We also discuss the family's impact on tumor immunity and potential therapeutic strategies.
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Affiliation(s)
- Yiming Luo
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Peking University Cancer Hospital and Institute, Beijing, China
| | - Ye Yuan
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Peking University Cancer Hospital and Institute, Beijing, China
| | - Dan Liu
- Early Drug Development Center, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Peking University Cancer Hospital and Institute, Beijing, China
| | - Haoxin Peng
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Peking University Cancer Hospital and Institute, Beijing, China
| | - Lin Shen
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Peking University Cancer Hospital and Institute, Beijing, China.
| | - Yang Chen
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Peking University Cancer Hospital and Institute, Beijing, China; Department of Gastrointestinal Cancer, Beijing GoBroad Hospital, Beijing 102200, China.
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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 2024:10.1007/s12094-024-03792-y. [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] [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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Tan X, Zhao X. B7-H3 in acute myeloid leukemia: From prognostic biomarker to immunotherapeutic target. Chin Med J (Engl) 2024; 137:2540-2551. [PMID: 38595093 PMCID: PMC11556994 DOI: 10.1097/cm9.0000000000003099] [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: 12/08/2023] [Indexed: 04/11/2024] Open
Abstract
ABSTRACT B7-H3 (CD276), an immune checkpoint protein of the B7 family, exhibits significant upregulation in solid tumors and hematologic malignancies, exerting a crucial role in their pathophysiology. The distinct differential expression of B7-H3 between tumors and normal tissues and its multifaceted involvement in tumor pathogenesis position it as a promising therapeutic target for tumors. In the context of acute myeloid leukemia (AML), B7-H3 is prominently overexpressed and closely associated with unfavorable prognoses, yet it has remained understudied. Despite various ongoing clinical trials demonstrating the potential efficacy of immunotherapies targeting B7-H3, the precise underlying mechanisms responsible for B7-H3-mediated proliferation and immune evasion in AML remain enigmatic. In view of this, we comprehensively outline the current research progress concerning B7-H3 in AML, encompassing in-depth discussions on its structural attributes, receptor interactions, expression profiles, and biological significance in normal tissues and AML. Moreover, we delve into the protumor effects of B7-H3 in AML, examine the intricate mechanisms that underlie its function, and discuss the emerging application of B7-H3-targeted therapy in AML treatment. By juxtaposing B7-H3 with other molecules within the B7 family, this review emphasizes the distinctive advantages of B7-H3, not only as a valuable prognostic biomarker but also as a highly promising immunotherapeutic target in AML.
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Affiliation(s)
- Xiao Tan
- Peking University People’s Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing 100044, China
| | - Xiangyu Zhao
- Peking University People’s Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing 100044, China
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5
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Perovic D, Dusanovic Pjevic M, Perovic V, Grk M, Rasic M, Milickovic M, Mijovic T, Rasic P. B7 homolog 3 in pancreatic cancer. World J Gastroenterol 2024; 30:3654-3667. [PMID: 39193002 PMCID: PMC11346158 DOI: 10.3748/wjg.v30.i31.3654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 07/24/2024] [Accepted: 08/06/2024] [Indexed: 08/13/2024] Open
Abstract
Despite advances in cancer treatment, pancreatic cancer (PC) remains a disease with high mortality rates and poor survival outcomes. The B7 homolog 3 (B7-H3) checkpoint molecule is overexpressed among many malignant tumors, including PC, with low or absent expression in healthy tissues. By modulating various immunological and nonimmunological molecular mechanisms, B7-H3 may influence the progression of PC. However, the impact of B7-H3 on the survival of patients with PC remains a subject of debate. Still, most available scientific data recognize this molecule as a suppressive factor to antitumor immunity in PC. Furthermore, it has been demonstrated that B7-H3 stimulates the migration, invasion, and metastasis of PC cells, and enhances resistance to chemotherapy. In preclinical models of PC, B7-H3-targeting monoclonal antibodies have exerted profound antitumor effects by increasing natural killer cell-mediated antibody-dependent cellular cytotoxicity and delivering radioisotopes and cytotoxic drugs to the tumor site. Finally, PC treatment with B7-H3-targeting antibody-drug conjugates and chimeric antigen receptor T cells is being tested in clinical studies. This review provides a comprehensive analysis of all PC-related studies in the context of B7-H3 and points to deficiencies in the current data that should be overcome by future research.
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Affiliation(s)
- Dijana Perovic
- Institute of Human Genetics, Faculty of Medicine, University of Belgrade, Belgrade 11000, Serbia
| | - Marija Dusanovic Pjevic
- Institute of Human Genetics, Faculty of Medicine, University of Belgrade, Belgrade 11000, Serbia
| | - Vladimir Perovic
- Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Belgrade 11000, Serbia
| | - Milka Grk
- Institute of Human Genetics, Faculty of Medicine, University of Belgrade, Belgrade 11000, Serbia
| | - Milica Rasic
- Institute of Human Genetics, Faculty of Medicine, University of Belgrade, Belgrade 11000, Serbia
| | - Maja Milickovic
- Department of Abdominal Surgery, Mother and Child Health Care Institute of Serbia “Dr. Vukan Cupic”, Belgrade 11000, Serbia
- Faculty of Medicine, University of Belgrade, Belgrade 11000, Serbia
| | - Tanja Mijovic
- Department of Abdominal Surgery, Mother and Child Health Care Institute of Serbia “Dr. Vukan Cupic”, Belgrade 11000, Serbia
| | - Petar Rasic
- Department of Abdominal Surgery, Mother and Child Health Care Institute of Serbia “Dr. Vukan Cupic”, Belgrade 11000, Serbia
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6
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Wang Y, Ding W, Hao W, Gong L, Peng Y, Zhang J, Qian Z, Xu K, Cai W, Gao Y. CXCL3/TGF-β-mediated crosstalk between CAFs and tumor cells augments RCC progression and sunitinib resistance. iScience 2024; 27:110224. [PMID: 39040058 PMCID: PMC11261419 DOI: 10.1016/j.isci.2024.110224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Revised: 03/17/2024] [Accepted: 06/06/2024] [Indexed: 07/24/2024] Open
Abstract
Cancer-associated fibroblasts (CAFs) play a significant role in tumor development and treatment failure, yet the precise mechanisms underlying their contribution to renal cell carcinoma (RCC) remains underexplored. This study explored the interaction between CAFs and tumor cells, and related mechanisms. CAFs isolated from tumor tissues promoted the tumor progression and drugs resistance both in vivo and in vitro. Mechanistically, chemokine (C-X-C motif) ligand (CXCL) 3 secreted from CAFs mediated its effects. CXCL3 activated its receptor CXCR2 to active the downstream ERK1/2 signaling pathway, subsequently promoting epithelial-mesenchymal transition and cell stemness. Blocking the crosstalk between CAFs and tumor cells by CXCR2 inhibitor SB225002 attenuated the functions of CAFs. Furthermore, Renca cells facilitated the transformation of normal interstitial fibroblasts (NFs) into CAFs and the expression of CXCL3 through TGF-β-Smad2/3 signaling pathway. In turn, transformed NFs promoted the tumor progression and drug resistance of RCC. These findings may constitute potential therapeutic strategies for RCC treatment.
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Affiliation(s)
- Yunxia Wang
- School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Weihong Ding
- Department of Urology, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Wenjing Hao
- School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Luyao Gong
- School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Yeheng Peng
- School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Jun Zhang
- School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Zhiyu Qian
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Ke Xu
- Department of Urology, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Weimin Cai
- School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Yuan Gao
- School of Pharmacy, Fudan University, Shanghai 201203, China
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Shen B, Mei J, Xu R, Cai Y, Wan M, Zhou J, Ding J, Zhu Y. B7-H3 is associated with the armored-cold phenotype and predicts poor immune checkpoint blockade response in melanoma. Pathol Res Pract 2024; 256:155267. [PMID: 38520953 DOI: 10.1016/j.prp.2024.155267] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Revised: 03/09/2024] [Accepted: 03/17/2024] [Indexed: 03/25/2024]
Abstract
Melanoma is the most suitable tumor type for immunotherapy, but not all melanoma patients could respond to immunotherapy. B7 homolog 3 (B7-H3) belongs to the B7 family and is overexpressed in a number of malignant tumors, but the expression pattern of B7-H3 in melanoma has not been well summarized. The expression of B7-H3 was investigated in melanoma and its correlations with features of the tumor microenvironment (TME) by using various public databases, including the Cancer Genome Atlas (TCGA), the GEPIA, and the Human Protein Atlas databases. In addition, the in-house melanoma tissue microarray was applied to validate the results from public databases. Based on the public and in-house cohorts, we found that B7-H3 was overexpressed in melanoma tumor tissues and high B7-H3 expression was related to poor clinical outcome. Moreover, B7-H3 was negatively correlated with levels of tumor-infiltrating lymphocytes (TILs) and positively correlated with collagen infiltration. With clinical translational value, the predictive value of B7-H3 for conventional immunotherapy was detected using the Kaplan-Meier plotter tool, and the results showed that melanoma patients with high B7-H3 expression were insensitive to anti-PD-1 and anti-CTLA-4 immunotherapy. In conclusion, we first investigate the expression of B7-H3 in melanoma and its correlations with the TME features, and indicate B7-H3 as a promising therapeutic target in melanoma patients that are insensitive to conventional immunotherapy.
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Affiliation(s)
- Bozhi Shen
- The First Clinical Medicine College, Nanjing Medical University, Nanjing 211166, China; The Laboratory Center for Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, China
| | - Jie Mei
- The First Clinical Medicine College, Nanjing Medical University, Nanjing 211166, China
| | - Rui Xu
- The First Clinical Medicine College, Nanjing Medical University, Nanjing 211166, China
| | - Yun Cai
- Department of Laboratory Medicine, Changzhou Jintan First People's Hospital, Changzhou 213200, China
| | - Mengyun Wan
- Department of Physiology, Nanjing Medical University, Nanjing 211166, China
| | - Ji Zhou
- Department of Physiology, Nanjing Medical University, Nanjing 211166, China
| | - Junli Ding
- Department of Oncology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi Medical Center, Nanjing Medical University, Wuxi 214023, China.
| | - Yichao Zhu
- Department of Physiology, Nanjing Medical University, Nanjing 211166, China.
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Jiang Y, Liu J, Chen L, Qian Z, Zhang Y. A promising target for breast cancer: B7-H3. BMC Cancer 2024; 24:182. [PMID: 38326735 PMCID: PMC10848367 DOI: 10.1186/s12885-024-11933-3] [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: 11/22/2023] [Accepted: 01/29/2024] [Indexed: 02/09/2024] Open
Abstract
Breast cancer (BC) is the second-leading factor of mortality for women globally and is brought on by a variety of genetic and environmental causes. The conventional treatments for this disease have limitations, making it difficult to improve the lifespan of breast cancer patients. As a result, extensive research has been conducted over the past decade to find innovative solutions to these challenges. Targeting of the antitumor immune response through the immunomodulatory checkpoint protein B7 family has revolutionized cancer treatment and led to intermittent patient responses. B7-H3 has recently received attention because of its significant demodulation and its immunomodulatory effects in many cancers. Uncontrolled B7-H3 expression and a bad outlook are strongly associated, according to a substantial body of cancer research. Numerous studies have shown that BC has significant B7-H3 expression, and B7-H3 induces an immune evasion phenotype, consequently enhancing the survival, proliferation, metastasis, and drug resistance of BC cells. Thus, an innovative target for immunotherapy against BC may be the B7-H3 checkpoint.In this review, we discuss the structure and regulation of B7-H3 and its double costimulatory/coinhibitory function within the framework of cancer and normal physiology. Then we expound the malignant behavior of B7-H3 in BC and its role in the tumor microenvironment (TME) and finally focus on targeted drugs against B7-H3 that have opened new therapeutic opportunities in BC.
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Affiliation(s)
- Ying Jiang
- Department of Oncology, Wuxi Maternal and Child Health Care Hospital, Women's Hospital of Jiangnan University, Jiangnan University, Wuxi, 214002, China
| | - Jiayu Liu
- Department of Oncology, Wuxi Maternal and Child Health Care Hospital, Women's Hospital of Jiangnan University, Jiangnan University, Wuxi, 214002, China
| | - Lingyan Chen
- Wuxi Maternal and Child Health Hospital, Nanjing Medical University, Wuxi, 214000, China
| | - Zhiwen Qian
- Wuxi Maternal and Child Health Hospital, Nanjing Medical University, Wuxi, 214000, China
| | - Yan Zhang
- Department of Oncology, Wuxi Maternal and Child Health Care Hospital, Women's Hospital of Jiangnan University, Jiangnan University, Wuxi, 214002, China.
- Wuxi Maternal and Child Health Hospital, Nanjing Medical University, Wuxi, 214000, China.
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Mei J, Cai Y, Zhu H, Jiang Y, Fu Z, Xu J, Chen L, Yang K, Zhao J, Song C, Zhang Y, Mao W, Yin Y. High B7-H3 expression with low PD-L1 expression identifies armored-cold tumors in triple-negative breast cancer. NPJ Breast Cancer 2024; 10:11. [PMID: 38280882 PMCID: PMC10821876 DOI: 10.1038/s41523-024-00618-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2023] [Accepted: 01/06/2024] [Indexed: 01/29/2024] Open
Abstract
Triple-negative breast cancer (TNBC) is generally regarded as the most aggressive subtype among breast cancers, but exhibits higher chemotherapeutic and immunotherapeutic responses due to its unique immunogenicity. Thus, appropriate discrimination of subtypes is critical for guiding therapeutic options in clinical practice. In this research, using multiple in-house and public cohorts, we investigated the expression features and immuno-correlations of B7-H3 in breast cancer and checked the anti-tumor effect of the B7-H3 monoclonal antibody in a mouse model. We also developed a novel classifier combining B7-H3 and PD-L1 expression in TNBC. B7-H3 was revealed to be related to immuno-cold features and accumulated collagen in TNBC. In addition, targeting B7-H3 using the monoclonal antibody significantly suppressed mouse TNBC growth, reversed the armored-cold phenotype, and also boosted anti-PD-1 immunotherapy. In addition, patients with B7-H3 high and PD-L1 low expression showed the lowest anti-tumor immune infiltration, the highest collagen level, and the lowest therapeutic responses to multiple therapies, which mostly belong to armored-cold tumors. Overall, this research provides a novel subtyping strategy based on the combination of B7-H3/PD-L1 expression, which leads to a novel approach for the management of TNBC.
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Affiliation(s)
- Jie Mei
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 211166, China
- The First Clinical Medicine College, Nanjing Medical University, Wuxi, 214023, China
- Department of Oncology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, 214023, China
| | - Yun Cai
- Wuxi Maternal and Child Health Care Hospital, Wuxi Medical Center of Nanjing Medical University, Wuxi, 214023, China
| | - Hongjun Zhu
- Department of Oncology, Nantong Third People's Hospital Affiliated to Nantong University, Nantong, 226006, China
| | - Ying Jiang
- Department of Gynecology, The Obstetrics and Gynecology Hospital Affiliated to Jiangnan University, Wuxi, 214023, China
| | - Ziyi Fu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 211166, China
| | - Junying Xu
- Department of Oncology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, 214023, China
| | - Lingyan Chen
- Wuxi Maternal and Child Health Care Hospital, Wuxi Medical Center of Nanjing Medical University, Wuxi, 214023, China
| | - Kai Yang
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 211166, China
- The First Clinical Medicine College, Nanjing Medical University, Wuxi, 214023, China
- Department of Oncology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, 214023, China
| | - Jinlu Zhao
- Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
| | - Chenghu Song
- Department of Thoracic Surgery, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, 214023, China
| | - Yan Zhang
- Wuxi Maternal and Child Health Care Hospital, Wuxi Medical Center of Nanjing Medical University, Wuxi, 214023, China.
- Department of Gynecology, The Obstetrics and Gynecology Hospital Affiliated to Jiangnan University, Wuxi, 214023, China.
| | - Wenjun Mao
- Department of Thoracic Surgery, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, 214023, China.
| | - Yongmei Yin
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 211166, China.
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, 211166, China.
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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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Guo X, Chang M, Wang Y, Xing B, Ma W. B7-H3 in Brain Malignancies: Immunology and Immunotherapy. Int J Biol Sci 2023; 19:3762-3780. [PMID: 37564196 PMCID: PMC10411461 DOI: 10.7150/ijbs.85813] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Accepted: 07/13/2023] [Indexed: 08/12/2023] Open
Abstract
The immune checkpoint B7-H3 (CD276), a member of the B7 family with immunoregulatory properties, has been identified recently as a novel target for immunotherapy for refractory blood cancers and solid malignant tumors. While research on B7-H3 in brain malignancies is limited, there is growing interest in exploring its therapeutic potential in this context. B7-H3 plays a crucial role in regulating the functions of immune cells, cancer-associated fibroblasts, and endothelial cells within the tumor microenvironment, contributing to the creation of a pro-tumorigenic milieu. This microenvironment promotes uncontrolled cancer cell proliferation, enhanced metabolism, increased cancer stemness, and resistance to standard treatments. Blocking B7-H3 and terminating its immunosuppressive function is expected to improve anti-tumor immune responses and, in turn, ameliorate the progression of tumors. Results from preclinical or observative studies and early-phase trials targeting B7-H3 have revealed promising anti-tumor efficacy and acceptable toxicity in glioblastoma (GBM), diffuse intrinsic pontine glioma (DIPG), medulloblastoma, neuroblastoma, craniopharyngioma, atypical teratoid/rhabdoid tumor, and brain metastases. Ongoing clinical trials are now investigating the use of CAR-T cell therapy and antibody-drug conjugate therapy, either alone or in combination with standard treatments or other therapeutic approaches, targeting B7-H3 in refractory or recurrent GBMs, DIPGs, neuroblastomas, medulloblastomas, ependymomas, and metastatic brain tumors. These trials hold promise for providing effective treatment options for these challenging intracranial malignancies in both adult and pediatric populations.
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Affiliation(s)
- Xiaopeng Guo
- Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Mengqi Chang
- Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
- Medical Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Yu Wang
- Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Bing Xing
- Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Wenbin Ma
- Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
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12
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Bottino C, Vitale C, Dondero A, Castriconi R. B7-H3 in Pediatric Tumors: Far beyond Neuroblastoma. Cancers (Basel) 2023; 15:3279. [PMID: 37444389 DOI: 10.3390/cancers15133279] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 06/16/2023] [Accepted: 06/20/2023] [Indexed: 07/15/2023] Open
Abstract
B7-H3 is a 4Ig transmembrane protein that emerged as a tumor-associated antigen in neuroblastoma. It belongs to the B7 family, shows an immunoregulatory role toward NK and T cells, and, therefore, has been included in the growing family of immune checkpoints. Besides neuroblastoma, B7-H3 is expressed by many pediatric cancers including tumors of the central nervous system, sarcomas, and acute myeloid leukemia. In children, particularly those affected by solid tumors, the therapeutic protocols are aggressive and cause important life-threatening side effects. Moreover, despite the improved survival observed in the last decade, a relevant number of patients show therapy resistance and fatal relapses. Immunotherapy represents a new frontier in the cure of cancer patients and the targeting of tumor antigens or immune checkpoints blockade showed exciting results in adults. In this encouraging scenario, researchers and clinicians are exploring the possibility to use immunotherapeutics targeting B7-H3; these include mAbs and chimeric antigen receptor T-cells (CAR-T). These tools are rapidly evolving to improve the efficacy and decrease the unwanted side effects; drug-conjugated mAbs, bi-tri-specific mAbs or CAR-T, and, very recently, NK cell engagers (NKCE), tetra-specific molecules engaging a tumor-associated antigen and NK cells, have been generated. Preclinical data are promising, and clinical trials are ongoing. Hopefully, the B7-H3 targeting will provide important benefits to cancer patients.
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Affiliation(s)
- Cristina Bottino
- Department of Experimental Medicine (DIMES), University of Genoa, 16132 Genoa, Italy
- Laboratory of Clinical and Experimental Immunology, IRCCS Istituto Giannina Gaslini, 16147 Genova, Italy
| | - Chiara Vitale
- Department of Experimental Medicine (DIMES), University of Genoa, 16132 Genoa, Italy
| | - Alessandra Dondero
- Department of Experimental Medicine (DIMES), University of Genoa, 16132 Genoa, Italy
| | - Roberta Castriconi
- Department of Experimental Medicine (DIMES), University of Genoa, 16132 Genoa, Italy
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13
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Thiery J. Modulation of the antitumor immune response by cancer-associated fibroblasts: mechanisms and targeting strategies to hamper their immunosuppressive functions. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2022; 3:598-629. [PMID: 36338519 PMCID: PMC9630350 DOI: 10.37349/etat.2022.00103] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Accepted: 07/21/2022] [Indexed: 11/16/2022] Open
Abstract
Cancer-associated fibroblasts (CAFs) are highly heterogeneous players that shape the tumor microenvironment and influence tumor progression, metastasis formation, and response to conventional therapies. During the past years, some CAFs subsets have also been involved in the modulation of immune cell functions, affecting the efficacy of both innate and adaptive anti-tumor immune responses. Consequently, the implication of these stromal cells in the response to immunotherapeutic strategies raised major concerns. In this review, current knowledge of CAFs origins and heterogeneity in the tumor stroma, as well as their effects on several immune cell populations that explain their immunosuppressive capabilities are summarized. The current development of therapeutic strategies for targeting this population and their implication in the field of cancer immunotherapy is also highlighted.
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Affiliation(s)
- Jerome Thiery
- INSERM, UMR 1186, 94800 Villejuif, France
- Gustave Roussy Cancer Campus, 94805 Villejuif, France
- University Paris Saclay, Faculty of Medicine, 94270 Le Kremlin Bicêtre, France
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14
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Zhao B, Li H, Xia Y, Wang Y, Wang Y, Shi Y, Xing H, Qu T, Wang Y, Ma W. Immune checkpoint of B7-H3 in cancer: from immunology to clinical immunotherapy. J Hematol Oncol 2022; 15:153. [PMID: 36284349 PMCID: PMC9597993 DOI: 10.1186/s13045-022-01364-7] [Citation(s) in RCA: 78] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Accepted: 09/30/2022] [Indexed: 11/28/2022] Open
Abstract
Immunotherapy for cancer is a rapidly developing treatment that modifies the immune system and enhances the antitumor immune response. B7-H3 (CD276), a member of the B7 family that plays an immunoregulatory role in the T cell response, has been highlighted as a novel potential target for cancer immunotherapy. B7-H3 has been shown to play an inhibitory role in T cell activation and proliferation, participate in tumor immune evasion and influence both the immune response and tumor behavior through different signaling pathways. B7-H3 expression has been found to be aberrantly upregulated in many different cancer types, and an association between B7-H3 expression and poor prognosis has been established. Immunotherapy targeting B7-H3 through different approaches has been developing rapidly, and many ongoing clinical trials are exploring the safety and efficacy profiles of these therapies in cancer. In this review, we summarize the emerging research on the function and underlying pathways of B7-H3, the expression and roles of B7-H3 in different cancer types, and the advances in B7-H3-targeted therapy. Considering different tumor microenvironment characteristics and results from preclinical models to clinical practice, the research indicates that B7-H3 is a promising target for future immunotherapy, which might eventually contribute to an improvement in cancer immunotherapy that will benefit patients.
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Affiliation(s)
- Binghao Zhao
- grid.506261.60000 0001 0706 7839Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730 People’s Republic of China ,grid.506261.60000 0001 0706 7839State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, People’s Republic of China
| | - Huanzhang Li
- grid.506261.60000 0001 0706 7839Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730 People’s Republic of China ,grid.506261.60000 0001 0706 7839State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, People’s Republic of China
| | - Yu Xia
- grid.506261.60000 0001 0706 7839Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730 People’s Republic of China ,grid.506261.60000 0001 0706 7839State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, People’s Republic of China
| | - Yaning Wang
- grid.506261.60000 0001 0706 7839Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730 People’s Republic of China ,grid.506261.60000 0001 0706 7839State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, People’s Republic of China
| | - Yuekun Wang
- grid.506261.60000 0001 0706 7839Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730 People’s Republic of China ,grid.506261.60000 0001 0706 7839State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, People’s Republic of China
| | - Yixin Shi
- grid.506261.60000 0001 0706 7839Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730 People’s Republic of China ,grid.506261.60000 0001 0706 7839State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, People’s Republic of China
| | - Hao Xing
- grid.506261.60000 0001 0706 7839Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730 People’s Republic of China ,grid.506261.60000 0001 0706 7839State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, People’s Republic of China
| | - Tian Qu
- grid.506261.60000 0001 0706 7839Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730 People’s Republic of China ,grid.506261.60000 0001 0706 7839State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, People’s Republic of China
| | - Yu Wang
- grid.506261.60000 0001 0706 7839Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730 People’s Republic of China ,grid.506261.60000 0001 0706 7839State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, People’s Republic of China
| | - Wenbin Ma
- grid.506261.60000 0001 0706 7839Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730 People’s Republic of China ,grid.506261.60000 0001 0706 7839State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, People’s Republic of China
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15
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Qi J, Sun H, Zhang Y, Wang Z, Xun Z, Li Z, Ding X, Bao R, Hong L, Jia W, Fang F, Liu H, Chen L, Zhong J, Zou D, Liu L, Han L, Ginhoux F, Liu Y, Ye Y, Su B. Single-cell and spatial analysis reveal interaction of FAP + fibroblasts and SPP1 + macrophages in colorectal cancer. Nat Commun 2022; 13:1742. [PMID: 35365629 PMCID: PMC8976074 DOI: 10.1038/s41467-022-29366-6] [Citation(s) in RCA: 389] [Impact Index Per Article: 129.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Accepted: 03/11/2022] [Indexed: 02/07/2023] Open
Abstract
Colorectal cancer (CRC) is among the most common malignancies with limited treatments other than surgery. The tumor microenvironment (TME) profiling enables the discovery of potential therapeutic targets. Here, we profile 54,103 cells from tumor and adjacent tissues to characterize cellular composition and elucidate the potential origin and regulation of tumor-enriched cell types in CRC. We demonstrate that the tumor-specific FAP+ fibroblasts and SPP1+ macrophages were positively correlated in 14 independent CRC cohorts containing 2550 samples and validate their close localization by immuno-fluorescent staining and spatial transcriptomics. This interaction might be regulated by chemerin, TGF-β, and interleukin-1, which would stimulate the formation of immune-excluded desmoplasic structure and limit the T cell infiltration. Furthermore, we find patients with high FAP or SPP1 expression achieved less therapeutic benefit from an anti-PD-L1 therapy cohort. Our results provide a potential therapeutic strategy by disrupting FAP+ fibroblasts and SPP1+ macrophages interaction to improve immunotherapy. Tumour microenvironment profiling during colorectal cancer progression may enable the discovery of therapeutic targets. Here, single cell and spatial RNA sequencing of tumour and adjacent normal tissues reveals an interaction between FAP+ fibroblasts and SPP1+ macrophages that could be disrupted as an immunotherapy strategy.
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Affiliation(s)
- Jingjing Qi
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, and the Ministry of Education Key Laboratory of Cell Death and Differentiation, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Jiao Tong University School of Medicine-Yale Institute for Immune Metabolism, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Department of Biliary and Pancreatic Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hongxiang Sun
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, and the Ministry of Education Key Laboratory of Cell Death and Differentiation, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Jiao Tong University School of Medicine-Yale Institute for Immune Metabolism, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yao Zhang
- Department of Gastroenterology, Center for Immune-related Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhengting Wang
- Department of Gastroenterology, Center for Immune-related Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhenzhen Xun
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, and the Ministry of Education Key Laboratory of Cell Death and Differentiation, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ziyi Li
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, and the Ministry of Education Key Laboratory of Cell Death and Differentiation, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xinyu Ding
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, and the Ministry of Education Key Laboratory of Cell Death and Differentiation, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Rujuan Bao
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, and the Ministry of Education Key Laboratory of Cell Death and Differentiation, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Liwen Hong
- Department of Gastroenterology, Center for Immune-related Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wenqing Jia
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, and the Ministry of Education Key Laboratory of Cell Death and Differentiation, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Fei Fang
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, and the Ministry of Education Key Laboratory of Cell Death and Differentiation, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hongzhi Liu
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, and the Ministry of Education Key Laboratory of Cell Death and Differentiation, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Jiao Tong University School of Medicine-Yale Institute for Immune Metabolism, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lei Chen
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, and the Ministry of Education Key Laboratory of Cell Death and Differentiation, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jie Zhong
- Department of Gastroenterology, Center for Immune-related Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Duowu Zou
- Department of Gastroenterology, Center for Immune-related Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lianxin Liu
- Department of Hepatobiliary Surgery, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, China
| | - Leng Han
- Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX, 77030, USA
| | - Florent Ginhoux
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, and the Ministry of Education Key Laboratory of Cell Death and Differentiation, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Singapore Immunology Network (SIgN), A*STAR, 8A Biomedical Grove, Immunos Building, Level 3 and 4, Singapore, 138648, Singapore
| | - Yingbin Liu
- Department of Biliary and Pancreatic Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Youqiong Ye
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, and the Ministry of Education Key Laboratory of Cell Death and Differentiation, Shanghai Jiao Tong University School of Medicine, Shanghai, China. .,Shanghai Jiao Tong University School of Medicine-Yale Institute for Immune Metabolism, Shanghai Jiao Tong University School of Medicine, Shanghai, China. .,Department of Gastroenterology, Center for Immune-related Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Bing Su
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, and the Ministry of Education Key Laboratory of Cell Death and Differentiation, Shanghai Jiao Tong University School of Medicine, Shanghai, China. .,Shanghai Jiao Tong University School of Medicine-Yale Institute for Immune Metabolism, Shanghai Jiao Tong University School of Medicine, Shanghai, China. .,Department of Gastroenterology, Center for Immune-related Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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16
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Sun M, Xie J, Zhang D, Chen C, Lin S, Chen Y, Zhang G. B7-H3 inhibits apoptosis of gastric cancer cell by interacting with Fibronectin. J Cancer 2022; 12:7518-7526. [PMID: 35003371 PMCID: PMC8734419 DOI: 10.7150/jca.59263] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Accepted: 10/06/2021] [Indexed: 01/14/2023] Open
Abstract
Anti-apoptosis has been widely accepted as a hallmark of malignancy. B7-H3, a type I transmembrane protein, plays a key role in anti-apoptosis and immune escape, but its regulation during cancer development remains unclear. To investigate how the effect of anti-apoptosis is regulated by B7-H3 in gastric cancer, we stably knocked down B7-H3 gene by shRNA in MGC-803 and MKN-45 cells. The correlation between B7-H3 and Fibronectin (FN) expression were investigated by bioinformatics in public data from TCGA (The Cancer Genome Atlas). Here, we reported that B7-H3 expression is positively correlated with FN in clinical gastric cancer samples, and B7-H3 promoted adhesion and inhibited apoptosis of gastric cancer cell through an FN-dependent pathway. Mechanistically, B7-H3 interacted with FN and subsequently activated PI3K/AKT signaling pathway, a critical mediator of oncogenic signaling. In addition, exogenous FN could inhibit the expression of pro-apoptosis-related proteins such as Caspase 3, Caspase 8, Caspase 9, Bax , p53, Apaf-1 and Cleaved PARP, and upregulated the levels of signal molecule p-PI3K, p-AKT and anti-apoptotic proteins Bcl-2 in B7-H3high group, as compared with those in B7-H3low group. In conclusion, we here for the first time revealed that B7-H3 inhibits apoptosis of gastric cancer cell through regulation of FN-mediated PI3K/AKT signaling pathways.
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Affiliation(s)
- Meiyun Sun
- Medical College of Soochow University, 199 Ren ai Road, Suzhou, Jiangsu Province, 215100, China.,Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, 708 Ren min Road, Suzhou, Jiangsu Province, 215100, China
| | - Jinjing Xie
- Medical College of Soochow University, 199 Ren ai Road, Suzhou, Jiangsu Province, 215100, China.,Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, 708 Ren min Road, Suzhou, Jiangsu Province, 215100, China
| | - Dongze Zhang
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, 708 Ren min Road, Suzhou, Jiangsu Province, 215100, China
| | - Chunyang Chen
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, 708 Ren min Road, Suzhou, Jiangsu Province, 215100, China
| | - Simin Lin
- Medical College of Soochow University, 199 Ren ai Road, Suzhou, Jiangsu Province, 215100, China.,Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, 708 Ren min Road, Suzhou, Jiangsu Province, 215100, China
| | - Yan Chen
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, 708 Ren min Road, Suzhou, Jiangsu Province, 215100, China
| | - Guangbo Zhang
- Medical College of Soochow University, 199 Ren ai Road, Suzhou, Jiangsu Province, 215100, China.,Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, 708 Ren min Road, Suzhou, Jiangsu Province, 215100, China
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17
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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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18
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Sun MY, Xie JJ, Zhang DZ, Zhang GB. [Preliminary study on the effect of B7H3 interaction with fibronectin on apoptosis of human chronic myeloid leukemia cells]. ZHONGHUA XUE YE XUE ZA ZHI = ZHONGHUA XUEYEXUE ZAZHI 2021; 42:939-944. [PMID: 35045656 PMCID: PMC8763590 DOI: 10.3760/cma.j.issn.0253-2727.2021.11.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Indexed: 11/05/2022]
Abstract
Objective: To explore the effect of the interaction between B7H3 and fibronectin (FN) on the apoptosis of human chronic myeloid leukemia K562 cells. Methods: The expression of B7H3 molecules in K562 cells was detected using flow cytometry and B7H3 overexpressing cells were constructed. The interaction between B7H3 and FN was detected using the co-immunoprecipitation technology. After adding exogenous FN, cell experiments were performed to detect changes in adhesion and cell apoptosis. The changes in apoptosis-related proteins and PI3K/AKT signaling pathway were detected using Western blot. Results: The expression of B7H3 was low in K562, and the cell line K562 OE (overexpression) -B7H3 and the control cell line K562 NC (negative control) -B7H3 were obtained after lentivirus transfection. There is an interaction between B7H3 and FN (P=0.036) , and this interaction promoted cell adhesion (P<0.05) , inhibited cell apoptosis (P<0.05) , and activated the PI3K/AKT signaling pathway (P<0.05) . Conclusion: B7H3 interacts with FN to promote cell adhesion and may inhibit K562 cell apoptosis by activating the PI3K/AKT signaling pathway.
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Affiliation(s)
- M Y Sun
- Department of Medicine, Soochow University, Suzhou 216007, China Jiangsu Key Laboratory of Clinical Immunology, Suzhou 216007, China
| | - J J Xie
- Department of Medicine, Soochow University, Suzhou 216007, China Jiangsu Key Laboratory of Clinical Immunology, Suzhou 216007, China
| | - D Z Zhang
- Jiangsu Key Laboratory of Clinical Immunology, Suzhou 216007, China The First Affiliated Hospital of Soochow University, Suzhou 216007, China
| | - G B Zhang
- Jiangsu Key Laboratory of Clinical Immunology, Suzhou 216007, China The First Affiliated Hospital of Soochow University, Suzhou 216007, China
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19
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Mao X, Xu J, Wang W, Liang C, Hua J, Liu J, Zhang B, Meng Q, Yu X, Shi S. Crosstalk between cancer-associated fibroblasts and immune cells in the tumor microenvironment: new findings and future perspectives. Mol Cancer 2021; 20:131. [PMID: 34635121 PMCID: PMC8504100 DOI: 10.1186/s12943-021-01428-1] [Citation(s) in RCA: 1139] [Impact Index Per Article: 284.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 09/11/2021] [Indexed: 01/04/2023] Open
Abstract
Cancer-associated fibroblasts (CAFs), a stromal cell population with cell-of-origin, phenotypic and functional heterogeneity, are the most essential components of the tumor microenvironment (TME). Through multiple pathways, activated CAFs can promote tumor growth, angiogenesis, invasion and metastasis, along with extracellular matrix (ECM) remodeling and even chemoresistance. Numerous previous studies have confirmed the critical role of the interaction between CAFs and tumor cells in tumorigenesis and development. However, recently, the mutual effects of CAFs and the tumor immune microenvironment (TIME) have been identified as another key factor in promoting tumor progression. The TIME mainly consists of distinct immune cell populations in tumor islets and is highly associated with the antitumor immunological state in the TME. CAFs interact with tumor-infiltrating immune cells as well as other immune components within the TIME via the secretion of various cytokines, growth factors, chemokines, exosomes and other effector molecules, consequently shaping an immunosuppressive TME that enables cancer cells to evade surveillance of the immune system. In-depth studies of CAFs and immune microenvironment interactions, particularly the complicated mechanisms connecting CAFs with immune cells, might provide novel strategies for subsequent targeted immunotherapies. Herein, we shed light on recent advances regarding the direct and indirect crosstalk between CAFs and infiltrating immune cells and further summarize the possible immunoinhibitory mechanisms induced by CAFs in the TME. In addition, we present current related CAF-targeting immunotherapies and briefly describe some future perspectives on CAF research in the end.
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Affiliation(s)
- Xiaoqi Mao
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong'An Road, Xuhui District, Shanghai, 200032, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.,Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China.,Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
| | - Jin Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong'An Road, Xuhui District, Shanghai, 200032, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.,Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China.,Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
| | - Wei Wang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong'An Road, Xuhui District, Shanghai, 200032, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.,Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China.,Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
| | - Chen Liang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong'An Road, Xuhui District, Shanghai, 200032, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.,Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China.,Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
| | - Jie Hua
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong'An Road, Xuhui District, Shanghai, 200032, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.,Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China.,Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
| | - Jiang Liu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong'An Road, Xuhui District, Shanghai, 200032, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.,Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China.,Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
| | - Bo Zhang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong'An Road, Xuhui District, Shanghai, 200032, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.,Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China.,Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
| | - Qingcai Meng
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong'An Road, Xuhui District, Shanghai, 200032, China. .,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China. .,Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China. .,Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China.
| | - Xianjun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong'An Road, Xuhui District, Shanghai, 200032, China. .,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China. .,Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China. .,Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China.
| | - Si Shi
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong'An Road, Xuhui District, Shanghai, 200032, China. .,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China. .,Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China. .,Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China.
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20
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Tang XY, Shi AP, Xiong YL, Zheng KF, Liu YJ, Shi XG, Jiang T, Zhao JB. Clinical Research on the Mechanisms Underlying Immune Checkpoints and Tumor Metastasis. Front Oncol 2021; 11:693321. [PMID: 34367975 PMCID: PMC8339928 DOI: 10.3389/fonc.2021.693321] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2021] [Accepted: 07/07/2021] [Indexed: 12/13/2022] Open
Abstract
This study highlights aspects of the latest clinical research conducted on the relationship between immune checkpoints and tumor metastasis. The overview of each immune checkpoint is divided into the following three sections: 1) structure and expression; 2) immune mechanism related to tumor metastasis; and 3) clinical research related to tumor metastasis. This review expands on the immunological mechanisms of 17 immune checkpoints, including TIM-3, CD47, and OX-40L, that mediate tumor metastasis; evidence shows that most of these immune checkpoints are expressed on the surface of T cells, which mainly exert immunomodulatory effects. Additionally, we have summarized the roles of these immune checkpoints in the diagnosis and treatment of metastatic tumors, as these checkpoints are considered common predictors of metastasis in various cancers such as prostate cancer, non-Hodgkin lymphoma, and melanoma. Moreover, certain immune checkpoints can be used in synergy with PD-1 and CTLA-4, along with the implementation of combination therapies such as LIGHT-VTR and anti-PD-1 antibodies. Presently, most monoclonal antibodies generated against immune checkpoints are under investigation as part of ongoing preclinical or clinical trials conducted to evaluate their efficacy and safety to establish a better combination treatment strategy; however, no significant progress has been made regarding monoclonal antibody targeting of CD28, VISTA, or VTCN1. The application of immune checkpoint inhibitors in early stage tumors to prevent tumor metastasis warrants further evidence; the immune-related adverse events should be considered before combination therapy. This review aims to elucidate the mechanisms of immune checkpoint and the clinical progress on their use in metastatic tumors reported over the last 5 years, which may provide insights into the development of novel therapeutic strategies that will assist with the utilization of various immune checkpoint inhibitors.
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Affiliation(s)
- Xi-Yang Tang
- Department of Thoracic Surgery, Tangdu Hospital, Air Force Medical University, Xi’an, China
| | - An-Ping Shi
- Department of Radiology & Functional and Molecular Imaging Key Lab of Shaanxi Province, Tangdu Hospital, Fourth Military Medical University (Air Force Medical University), Xi’an, China
| | - Yan-Lu Xiong
- Department of Thoracic Surgery, Tangdu Hospital, Air Force Medical University, Xi’an, China
| | - Kai-Fu Zheng
- Department of Thoracic Surgery, Tangdu Hospital, Air Force Medical University, Xi’an, China
| | - Yu-Jian Liu
- Department of Thoracic Surgery, Tangdu Hospital, Air Force Medical University, Xi’an, China
| | - Xian-Gui Shi
- College of Basic Medicine, Air Force Medical University, Xi’an, China
| | - Tao Jiang
- Department of Thoracic Surgery, Tangdu Hospital, Air Force Medical University, Xi’an, China
| | - Jin-Bo Zhao
- Department of Thoracic Surgery, Tangdu Hospital, Air Force Medical University, Xi’an, China
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21
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Wu F, Yang J, Liu J, Wang Y, Mu J, Zeng Q, Deng S, Zhou H. Signaling pathways in cancer-associated fibroblasts and targeted therapy for cancer. Signal Transduct Target Ther 2021; 6:218. [PMID: 34108441 PMCID: PMC8190181 DOI: 10.1038/s41392-021-00641-0] [Citation(s) in RCA: 348] [Impact Index Per Article: 87.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 04/20/2021] [Accepted: 05/06/2021] [Indexed: 02/05/2023] Open
Abstract
To flourish, cancers greatly depend on their surrounding tumor microenvironment (TME), and cancer-associated fibroblasts (CAFs) in TME are critical for cancer occurrence and progression because of their versatile roles in extracellular matrix remodeling, maintenance of stemness, blood vessel formation, modulation of tumor metabolism, immune response, and promotion of cancer cell proliferation, migration, invasion, and therapeutic resistance. CAFs are highly heterogeneous stromal cells and their crosstalk with cancer cells is mediated by a complex and intricate signaling network consisting of transforming growth factor-beta, phosphoinositide 3-kinase/AKT/mammalian target of rapamycin, mitogen-activated protein kinase, Wnt, Janus kinase/signal transducers and activators of transcription, epidermal growth factor receptor, Hippo, and nuclear factor kappa-light-chain-enhancer of activated B cells, etc., signaling pathways. These signals in CAFs exhibit their own special characteristics during the cancer progression and have the potential to be targeted for anticancer therapy. Therefore, a comprehensive understanding of these signaling cascades in interactions between cancer cells and CAFs is necessary to fully realize the pivotal roles of CAFs in cancers. Herein, in this review, we will summarize the enormous amounts of findings on the signals mediating crosstalk of CAFs with cancer cells and its related targets or trials. Further, we hypothesize three potential targeting strategies, including, namely, epithelial-mesenchymal common targets, sequential target perturbation, and crosstalk-directed signaling targets, paving the way for CAF-directed or host cell-directed antitumor therapy.
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Affiliation(s)
- Fanglong Wu
- State Key Laboratory of Oral Diseases, National Center of Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Jin Yang
- State Key Laboratory of Oral Diseases, National Center of Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Junjiang Liu
- State Key Laboratory of Oral Diseases, National Center of Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Ye Wang
- State Key Laboratory of Oral Diseases, National Center of Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Jingtian Mu
- State Key Laboratory of Oral Diseases, National Center of Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Qingxiang Zeng
- State Key Laboratory of Oral Diseases, National Center of Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Shuzhi Deng
- State Key Laboratory of Oral Diseases, National Center of Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Hongmei Zhou
- State Key Laboratory of Oral Diseases, National Center of Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People's Republic of China.
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22
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Kim K, Jung JH, Yoo HJ, Hyun JK, Park JH, Na D, Yeon JH. Anti-Metastatic Effects of Plant Sap-Derived Extracellular Vesicles in a 3D Microfluidic Cancer Metastasis Model. J Funct Biomater 2020; 11:jfb11030049. [PMID: 32650517 PMCID: PMC7563847 DOI: 10.3390/jfb11030049] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 06/07/2020] [Accepted: 06/23/2020] [Indexed: 12/12/2022] Open
Abstract
Natural medicinal plants have attracted considerable research attention for their potential as effective drugs. The roots, leaves and stems of the plant, Dendropanax morbifera, which is endemic to southern regions of Asia, have long been used as a folk medicine to treat variety of diseases. However, the sap of this plant has not been widely studied and its bioactive properties have yet to be clearly elucidated. Here, we isolated extracellular vesicles from D. morbifera sap with the goal of improving the intracellular delivery efficiency and clinical effectiveness of bioactive compounds in D. morbifera sap. We further investigated the anti-metastatic effects of D. morbifera sap-derived extracellular vesicles (DMS-EVs) using a cancer metastasis model based on 3D microfluidic system that closely mimics the in vivo tumor environment. We found that DMS-EVs exerted a concentration-dependent suppressive effect on cancer-associated fibroblasts (CAFs), which are important mediators of cancer metastasis. DMS-EVs also altered expression level of genes, especially growth factor and extracellular matrix (ECM)-related genes, including integrin and collagen. Our findings suggest that DMS-EVs can act as anti-CAF agents to reduce CAFs in the tumor microenvironment. They further indicate the utility of our 3D microfluidic model for various drug-screening assays as a potential alternative to animal testing for use in validating therapeutic effects on cancer metastasis.
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Affiliation(s)
- Kimin Kim
- Department of Integrative Biosciences, University of Brain Education, Cheonan 31228, Korea; (K.K.); (H.J.Y.)
| | - Jik-Han Jung
- Department of Bio and Brain engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Korea; (J.-H.J.); (J.-H.P.)
| | - Hye Ju Yoo
- Department of Integrative Biosciences, University of Brain Education, Cheonan 31228, Korea; (K.K.); (H.J.Y.)
| | - Jae-Kyung Hyun
- Electron Microscopy Research Center, Korea Basic Science Institute, Cheongju 28119, Korea;
| | - Ji-Ho Park
- Department of Bio and Brain engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Korea; (J.-H.J.); (J.-H.P.)
| | - Dokyun Na
- School of Integrative Engineering, Chung-Ang University, Seoul 06911, Korea;
| | - Ju Hun Yeon
- Department of Integrative Biosciences, University of Brain Education, Cheonan 31228, Korea; (K.K.); (H.J.Y.)
- Correspondence: ; Tel.: +82-41-529-2621; Fax: +82-41-529-2674
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Zhong C, Tao B, Chen Y, Guo Z, Yang X, Peng L, Xia X, Chen L. B7-H3 Regulates Glioma Growth and Cell Invasion Through a JAK2/STAT3/Slug-Dependent Signaling Pathway. Onco Targets Ther 2020; 13:2215-2224. [PMID: 32210587 PMCID: PMC7075435 DOI: 10.2147/ott.s237841] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2019] [Accepted: 02/24/2020] [Indexed: 12/24/2022] Open
Abstract
Purpose The aim of this study was to explore the potential role of B7-H3 in malignant glioma progression and identify an innovative approach in clinical glioma therapy. Methods The protein expression of B7-H3 in high- and low-grade tumor tissues from glioma patients was assessed by immunohistochemistry. The proliferative and invasive ability of B7-H3-overexpressing or knockout glioma cells was analyzed in vitro and in vivo by CCK-8 assay and an orthotopic mouse glioma model, respectively. Activation of the JAK2/STAT3/Slug signaling pathway and epithelial-mesenchymal transition (EMT) was examined by Western blotting and immunofluorescence. The anticancer effects of napabucasin (NAP) and temozolomide (TMZ) were analyzed in an orthotopic mouse glioma model. Results The expression of B7-H3 was higher in high-grade than in low-grade tumor tissues from glioma patients. In line with this, overexpression of B7-H3 enhanced glioma cell proliferation, induced sustained glioma growth, and promoted glioma cell invasion in vitro and in vivo. Moreover, these effects were mediated through the activation of the JAK2/STAT3/Slug signaling pathway in B7-H3 overexpression glioma cells. We also found that B7-H3 induced EMT processes through downregulation of E-cadherin and upregulation of MMP-2/-9 expression, resulting in enhanced invasion of glioma cells. Finally, we show that the combination of NAP and TMZ significantly suppressed glioma growth and glioma cell invasion, both in vitro and in vivo. Conclusion B7-H3 overexpression facilitated sustained glioma growth and promoted glioma cell invasion through a JAK2/STAT3/Slug-dependent signaling pathway. Application of the STAT3 inhibitor NAP significantly suppressed glioma growth and invasion, and has potential as a therapeutic strategy for the treatment of glioma.
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Affiliation(s)
- Chuanhong Zhong
- Neurosurgery Department, Affiliated Hospital of Southwest Medical University, Luzhou, People's Republic of China.,Neurosurgical Clinical Medical Research Center of Sichuan Province, Luzhou, People's Republic of China
| | - Bei Tao
- Rheumatism Department, Affiliated Hospital of Southwest Medical University, Luzhou, People's Republic of China
| | - Yitian Chen
- Department of Clinical Medicine, Medical College of Soochow University, Suzhou, People's Republic of China
| | - Zhangchao Guo
- Neurosurgery Department, Affiliated Hospital of Southwest Medical University, Luzhou, People's Republic of China
| | - Xiaobo Yang
- Neurosurgery Department, Affiliated Hospital of Southwest Medical University, Luzhou, People's Republic of China.,Neurosurgical Clinical Medical Research Center of Sichuan Province, Luzhou, People's Republic of China
| | - Lilei Peng
- Neurosurgery Department, Affiliated Hospital of Southwest Medical University, Luzhou, People's Republic of China.,Neurosurgical Clinical Medical Research Center of Sichuan Province, Luzhou, People's Republic of China
| | - Xiangguo Xia
- Neurosurgery Department, Affiliated Hospital of Southwest Medical University, Luzhou, People's Republic of China.,Neurosurgical Clinical Medical Research Center of Sichuan Province, Luzhou, People's Republic of China
| | - Ligang Chen
- Neurosurgery Department, Affiliated Hospital of Southwest Medical University, Luzhou, People's Republic of China.,Neurosurgical Clinical Medical Research Center of Sichuan Province, Luzhou, People's Republic of China
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