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1
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Liu H, Li G, Shen C, Qi X, Liu Y, Hua D, Mao Y, Zhang T. B7-H3-mediated deubiquitination stabilizing CYP1B1 expression promotes chemotherapy resistance in colorectal cancer. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167771. [PMID: 40057208 DOI: 10.1016/j.bbadis.2025.167771] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Revised: 02/12/2025] [Accepted: 02/27/2025] [Indexed: 04/15/2025]
Abstract
Colorectal cancer (CRC) is the second‑leading cause of cancer-related mortality worldwide. It is frequently characterized by chemotherapy resistance，which is a predominant factor contributing to unfavorable patient prognosis. B7-H3 is a novel tumor marker and a potential immunotherapy target. High B7-H3 expression in colorectal cancer is associated with adverse prognosis. In this study, we noted increased B7-H3 expression in colorectal cancer tumor tissues. Both in vivo and in vitro experiments demonstrated that increased B7-H3 expression promotes resistance to chemotherapy in CRC. Furthermore, our findings suggest that B7-H3 mediates CRC resistance by modulating CYP1B1 expression. Mechanistic investigations indicated that B7-H3 inhibited the ubiquitination of CYP1B1, stabilized its expression，and consequently enhanced chemotherapeutic resistance in CRC. In summary, our results underscore the significance of the B7-H3-CYP1B1 interaction as a crucial therapeutic target for overcoming chemotherapy resistance in CRC.
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Affiliation(s)
- Huan Liu
- Department of Oncology, Affiliated Hospital of Jiangnan University, Wuxi 214062, Jiangsu Province, China
| | - Guifang Li
- Department of Oncology, Affiliated Hospital of Jiangnan University, Wuxi 214062, Jiangsu Province, China
| | - Chenjie Shen
- Department of Oncology, Affiliated Hospital of Jiangnan University, Wuxi 214062, Jiangsu Province, China
| | - Xiaowei Qi
- Department of Pathology, Affiliated Hospital of Jiangnan University, Wuxi 214062, Jiangsu Province, China
| | - Yankui Liu
- Department of Pathology, Affiliated Hospital of Jiangnan University, Wuxi 214062, Jiangsu Province, China
| | - Dong Hua
- The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China
| | - Yong Mao
- Department of Oncology, Affiliated Hospital of Jiangnan University, Wuxi 214062, Jiangsu Province, China
| | - Ting Zhang
- Institute of Cancer, Affiliated Hospital of Jiangnan University, Wuxi 214062, Jiangsu Province, China; Peninsula Medical School, Faculty of Health, University of Plymouth, Plymouth PL6 8BU, Devon, UK.
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2
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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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3
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Seo YR, Kim HB, Jung H, Kim EG, Huh S, Yi EC, Kim KM. Unveiling transcriptional mechanisms of B7-H3 in breast cancer stem cells through proteomic approaches. iScience 2025; 28:112218. [PMID: 40230524 PMCID: PMC11995042 DOI: 10.1016/j.isci.2025.112218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Revised: 11/29/2024] [Accepted: 03/11/2025] [Indexed: 04/16/2025] Open
Abstract
B7-H3, an immune checkpoint molecule, is prominently overexpressed in various solid tumors, correlating with poor clinical outcomes. Despite its critical role in promoting tumorigenesis, metastasis, and immune evasion, the regulatory mechanisms governing B7-H3 expression, particularly in cancer stem cells (CSCs), remain elusive. In this comprehensive study, we focused on breast CSCs to uncover the transcriptional regulators driving B7-H3 overexpression. Utilizing DNA affinity purification-mass spectrometry (DAP-MS) to analyze B7-H3 promoter regions, we identified a novel set of transcription factors, including DDB1, XRCC5, PARP1, RPA1, and RPA3, as key modulators of B7-H3 expression. Functional assays revealed that targeting DDB1 with nitazoxanide significantly downregulated B7-H3 expression, subsequently impairing tumor sphere formation and cell migration in breast CSCs. These findings not only elucidate the complex transcriptional network controlling B7-H3 expression but also open new avenues for developing targeted immunotherapies aimed at disrupting CSC-driven cancer progression.
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Affiliation(s)
- Yu Ri Seo
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology and College of Medicine or College of Pharmacy, Seoul National University, Seoul, Republic of Korea
- Institute of Medical and Biological Engineering, Seoul National University Medical Research Center, Seoul, Republic of Korea
| | - Han Byeol Kim
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology and College of Medicine or College of Pharmacy, Seoul National University, Seoul, Republic of Korea
| | - Hyeryeon Jung
- Department of Bio-Health Convergence, Kangwon National University, Chuncheon, Republic of Korea
| | - Eunhee G. Kim
- Department of Systems Immunology, Division of Biomedical Convergence, College of Biomedical Science, Kangwon National University, Chuncheon, Republic of Korea
| | - Sumin Huh
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology and College of Medicine or College of Pharmacy, Seoul National University, Seoul, Republic of Korea
| | - Eugene C. Yi
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology and College of Medicine or College of Pharmacy, Seoul National University, Seoul, Republic of Korea
- Institute of Medical and Biological Engineering, Seoul National University Medical Research Center, Seoul, Republic of Korea
| | - Kristine M. Kim
- Department of Bio-Health Convergence, Kangwon National University, Chuncheon, Republic of Korea
- Department of Systems Immunology, Division of Biomedical Convergence, College of Biomedical Science, Kangwon National University, Chuncheon, Republic of Korea
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4
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Cao W, Zhang X, Chen J, Sun L, He H, Yu F. Codelivery of apigenin, FdUMP and CD276 antibody synergistic inhibit colorectal cancer by ferroptosis-apoptosis-pyroptosis and CD276 blockade. Asian J Pharm Sci 2025; 20:101016. [PMID: 40224726 PMCID: PMC11987651 DOI: 10.1016/j.ajps.2025.101016] [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: 09/14/2024] [Revised: 11/27/2024] [Accepted: 12/01/2024] [Indexed: 04/15/2025] Open
Abstract
Mitochondria provides adenosine triphosphate for multiple vital movements to ensure tumor cell proliferation. Compared to the broadly used method of inducing DNA replication arrest to kill cancer, inducing mitochondria damage to cause energy shortage is quite promising as it can inhibit tumor cell bioactivities, increase intracellular accumulation of toxic drugs, eventually sensitize chemotherapy and even reverse drug resistance. Breaking the balance of glutathione (GSH) and reactive oxygen species (ROS) contents have been proven efficient in destroying mitochondria respectively. Herein, apigenin, a GSH efflux reagent, and 2'-deoxy-5-fluorouridine 5'-monophosphate sodium salt (FdUMP) that could induce toxic ROS were co-delivered by constructed lipid nanoparticles, noted as Lip@AF. An immune-checkpoint inhibition reagent CD276 antibody was modified onto the surface of Lip@AF with high reaction specificity (noted as αCD276-Lip@AF) to enhance the recognition of immune cells to tumor. Results showed that the redox balance was destroyed, leading to severe injury to mitochondria and cell membrane. Furthermore, synergistic DNA/RNA replication inhibition caused by inhibiting the function of thymidylate synthase were observed. Eventually, significantly enhanced cytotoxicity was achieved by combining multiple mechanisms including ferroptosis, apoptosis and pyroptosis. In vivo, strengthen tumor growth inhibition was achieved by αCD276-Lip@AF with high biosafety, providing new sights in enhancing chemotherapy sensitiveness and achieving high-performance chemo-immunotherapy.
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Affiliation(s)
- Weiran Cao
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, International Joint Laboratory of Ocular Diseases, School of Pharmacy, School of Biomedical Engineering and Technology, Tianjin Medical University, Tianjin 300070, China
- Laboratory of Integrated Medicine Tumor Immunology, Shanxi University of Chinese Medicine, Taiyuan 030000, China
| | - Xue Zhang
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, International Joint Laboratory of Ocular Diseases, School of Pharmacy, School of Biomedical Engineering and Technology, Tianjin Medical University, Tianjin 300070, China
| | - Jiaxuan Chen
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, International Joint Laboratory of Ocular Diseases, School of Pharmacy, School of Biomedical Engineering and Technology, Tianjin Medical University, Tianjin 300070, China
| | - Lu Sun
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, International Joint Laboratory of Ocular Diseases, School of Pharmacy, School of Biomedical Engineering and Technology, Tianjin Medical University, Tianjin 300070, China
| | - Huining He
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, International Joint Laboratory of Ocular Diseases, School of Pharmacy, School of Biomedical Engineering and Technology, Tianjin Medical University, Tianjin 300070, China
| | - Fei Yu
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, International Joint Laboratory of Ocular Diseases, School of Pharmacy, School of Biomedical Engineering and Technology, Tianjin Medical University, Tianjin 300070, China
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5
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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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6
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Babič D, Jovčevska I, Zottel A. B7-H3 in glioblastoma and beyond: significance and therapeutic strategies. Front Immunol 2024; 15:1495283. [PMID: 39664380 PMCID: PMC11632391 DOI: 10.3389/fimmu.2024.1495283] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Accepted: 11/06/2024] [Indexed: 12/13/2024] Open
Abstract
Cancer has emerged as the second most prevalent disease and the leading cause of death, claiming the lives of 10 million individuals each year. The predominant varieties of cancer encompass breast, lung, colon, rectal, and prostate cancers. Among the more aggressive malignancies is glioblastoma, categorized as WHO stage 4 brain cancer. Following diagnosis, the typical life expectancy ranges from 12 to 15 months, as current established treatments like surgical intervention, radiotherapy, and chemotherapy using temozolomide exhibit limited effectiveness. Beyond conventional approaches, the exploration of immunotherapy for glioblastoma treatment is underway. A methodology involves CAR-T cells, monoclonal antibodies, ADCC and nanobodies sourced from camelids. Immunotherapy's recent focal point is the cellular ligand B7-H3, notably abundant in tumor cells while either scarce or absent in normal ones. Its expression elevates with cancer progression and serves as a promising prognostic marker. In this article, we delve into the essence of B7-H3, elucidating its function and involvement in signaling pathways. We delineate the receptors it binds to and its significance in glioblastoma and other cancer types. Lastly, we examine its role in immunotherapy and the utilization of nanobodies in this domain.
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7
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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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8
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Ranganathan S, Reddy A, Russo A, Malepelle U, Desai A. Double agents in immunotherapy: Unmasking the role of antibody drug conjugates in immune checkpoint targeting. Crit Rev Oncol Hematol 2024; 202:104472. [PMID: 39111458 DOI: 10.1016/j.critrevonc.2024.104472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Revised: 07/29/2024] [Accepted: 08/02/2024] [Indexed: 08/19/2024] Open
Abstract
Antibody-drug conjugates (ADCs) have high specificity with lesser off-target effects, thus providing improved efficacy over traditional chemotherapies. A total of 14 ADCs have been approved for use against cancer by the US Food and Drug Administration (FDA), with more than 100 ADCs currently in clinical trials. Of particular interest ADCs targeting immune antigens PD-L1, B7-H3, B7-H4 and integrins. Specifically, we describe ADCs in development along with the gene and protein expression of these immune checkpoints across a wide range of cancer types let url = window.clickTag || window.clickTag1 || window.clickTag2 || window.clickTag3 || window.clickTag4 || window.bsClickTAG || window.bsClickTAG1 || window.bsClickTAG2 || window.url || ''; if(typeof url == 'string'){ document.body.dataset['perxceptAdRedirectUrl'] = url;}.
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Affiliation(s)
| | | | | | - Umberto Malepelle
- Department of Public Health University Federico II of Naples, Naples, Italy
| | - Aakash Desai
- Division of Hematology and Oncology, Department of Medicine, University of Alabama, Birmingham, United States.
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9
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Perovic D, Dusanovic Pjevic M, Perovic V, Grk M, Rasic M, Milickovic M, Mijovic T, Rasic P. B7 homolog 3 in pancreatic cancer. World J Gastroenterol 2024; 30:3654-3667. [PMID: 39193002 PMCID: PMC11346158 DOI: 10.3748/wjg.v30.i31.3654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 07/24/2024] [Accepted: 08/06/2024] [Indexed: 08/13/2024] Open
Abstract
Despite advances in cancer treatment, pancreatic cancer (PC) remains a disease with high mortality rates and poor survival outcomes. The B7 homolog 3 (B7-H3) checkpoint molecule is overexpressed among many malignant tumors, including PC, with low or absent expression in healthy tissues. By modulating various immunological and nonimmunological molecular mechanisms, B7-H3 may influence the progression of PC. However, the impact of B7-H3 on the survival of patients with PC remains a subject of debate. Still, most available scientific data recognize this molecule as a suppressive factor to antitumor immunity in PC. Furthermore, it has been demonstrated that B7-H3 stimulates the migration, invasion, and metastasis of PC cells, and enhances resistance to chemotherapy. In preclinical models of PC, B7-H3-targeting monoclonal antibodies have exerted profound antitumor effects by increasing natural killer cell-mediated antibody-dependent cellular cytotoxicity and delivering radioisotopes and cytotoxic drugs to the tumor site. Finally, PC treatment with B7-H3-targeting antibody-drug conjugates and chimeric antigen receptor T cells is being tested in clinical studies. This review provides a comprehensive analysis of all PC-related studies in the context of B7-H3 and points to deficiencies in the current data that should be overcome by future research.
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Affiliation(s)
- Dijana Perovic
- Institute of Human Genetics, Faculty of Medicine, University of Belgrade, Belgrade 11000, Serbia
| | - Marija Dusanovic Pjevic
- Institute of Human Genetics, Faculty of Medicine, University of Belgrade, Belgrade 11000, Serbia
| | - Vladimir Perovic
- Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Belgrade 11000, Serbia
| | - Milka Grk
- Institute of Human Genetics, Faculty of Medicine, University of Belgrade, Belgrade 11000, Serbia
| | - Milica Rasic
- Institute of Human Genetics, Faculty of Medicine, University of Belgrade, Belgrade 11000, Serbia
| | - Maja Milickovic
- Department of Abdominal Surgery, Mother and Child Health Care Institute of Serbia “Dr. Vukan Cupic”, Belgrade 11000, Serbia
- Faculty of Medicine, University of Belgrade, Belgrade 11000, Serbia
| | - Tanja Mijovic
- Department of Abdominal Surgery, Mother and Child Health Care Institute of Serbia “Dr. Vukan Cupic”, Belgrade 11000, Serbia
| | - Petar Rasic
- Department of Abdominal Surgery, Mother and Child Health Care Institute of Serbia “Dr. Vukan Cupic”, Belgrade 11000, Serbia
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10
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Park R, Yu J, Shahzad M, Lee S, Ji JD. The immune regulatory function of B7-H3 in malignancy: spotlight on the IFN-STAT1 axis and regulation of tumor-associated macrophages. Immunol Res 2024; 72:526-537. [PMID: 38265550 DOI: 10.1007/s12026-024-09458-9] [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: 11/29/2023] [Accepted: 01/17/2024] [Indexed: 01/25/2024]
Abstract
B7-H3 is a member of the B7 superfamily and a putative inhibitory immune checkpoint molecule. Several early-phase clinical trials have reported promising anti-tumor activity and safety of anti-cancer drugs targeting B7-H3, suggesting that it may be a promising target for a potential next-generation immune checkpoint inhibitor. Despite ongoing clinical studies, most B7-H3-targeted drugs being currently investigated rely on direct cytotoxicity as their mechanisms of action rather than modulating its function as an immune checkpoint, at least in part due to its incompletely understood immune regulatory function. Recent studies have begun to elucidate the role of B7-H3 in regulating the tumor microenvironment (TME). Emerging evidence suggests that B7-H3 may regulate the interferon-STAT1 axis in the TME and promote immune suppression. Similarly, increasing evidence shows B7-H3 may be implicated in promoting M1 to M2 polarization of tumor-associated macrophages (TAMs). There is also accumulating evidence suggesting that B7-H3 may play a role in the heterotypic fusion of cancer stem cells and macrophages, thereby promoting tumor invasion and metastasis. Here, we review the recent advances in the understanding of B7-H3 cancer immunobiology with a focus on highlighting its potential role in the interferon priming of TAMs and the heterotypic fusion of TAMs with cancer stem cells and suggest future direction in elucidating its immune checkpoint function.
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Affiliation(s)
- Robin Park
- Department of Hematology/Oncology, Moffitt Cancer Center/University of South Florida, Tampa, FL, USA
| | - James Yu
- Department of Hematology/Oncology, Moffitt Cancer Center/University of South Florida, Tampa, FL, USA
| | - Moazzam Shahzad
- Department of Hematology/Oncology, Moffitt Cancer Center/University of South Florida, Tampa, FL, USA
| | - Sunggon Lee
- Department of Internal Medicine, Korea University, Seoul, South Korea
| | - Jong Dae Ji
- Department of Rheumatology, College of Medicine, Korea University, Seoul, South Korea.
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11
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Zhang ZY, Xu JH, Zhang JL, Lin YX, Ou-Yang J. Pro-cancer role of CD276 as a novel biomarker for clear cell renal cell carcinoma. Urol Oncol 2024; 42:247.e1-247.e10. [PMID: 38600002 DOI: 10.1016/j.urolonc.2024.03.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 03/21/2024] [Accepted: 03/28/2024] [Indexed: 04/12/2024]
Abstract
OBJECTIVE Renal cell carcinoma (RCC) is a common malignant tumor with a high incidence in males and the elderly, and clear cell RCC (ccRCC) is the most common RCC subtype. ccRCC is highly metastatic with a poor prognosis. Therefore, it is crucial to obtain a detailed understanding of the molecular mechanism of ccRCC and to identify suitable biomarkers to realize early diagnosis and improve prognosis. METHODS We analyzed data from the Cancer Genome Atlas, investigated the overall differential expression of CD276 in ccRCC, and evaluated the influence of CD276 on patient survival and prognosis. We also performed gene set enrichment analysis (GSEA) and pathway enrichment analysis and investigated cell infiltration and drug responsiveness to further assess the regulatory effect of CD276 on ccRCC. Furthermore, we verified CD276 expression in RCC cell lines and control cell lines. RESULTS The CD276 expression level in ccRCC samples was higher than that in corresponding samples adjacent to the tumors. Moreover, high CD276 expression levels were positively correlated with poor prognosis in patients with RCC. GSEA revealed that CD276 was significantly involved in immune-related pathways, and the level of CD276 expression was confirmed as associated with immune cell infiltration to some extent. Notably, some drugs were predicted to act on CD276, and this was confirmed by molecular docking. Furthermore, high levels of CD276 expression in RCC cell lines were verified. CONCLUSION CD276 expression was significantly increased in ccRCC tissues and cells and positively correlated with patient prognosis. CD276 is a potential prognostic biomarker of ccRCC. Overall, this study provides a potential therapeutic strategy for ccRCC.
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Affiliation(s)
- Zhi-Yu Zhang
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou 215000, Jiangsu, China
| | - Jian-Hao Xu
- Department of Pathology, The First People's Hospital of Kunshan, Suzhou 215300, Jiangsu, China
| | - Jiang-Lei Zhang
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou 215000, Jiangsu, China
| | - Yu-Xin Lin
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou 215000, Jiangsu, China
| | - Jun Ou-Yang
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou 215000, Jiangsu, China.
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12
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Wu S, Hu C, Hui K, Jiang X. Non-immune functions of B7-H3: bridging tumor cells and the tumor vasculature. Front Oncol 2024; 14:1408051. [PMID: 38952550 PMCID: PMC11215132 DOI: 10.3389/fonc.2024.1408051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Accepted: 06/04/2024] [Indexed: 07/03/2024] Open
Abstract
B7-H3 (CD276), an immune checkpoint molecule, is overexpressed in various types of cancer and their tumor vasculature, demonstrating significant associations with adverse clinical outcomes. In addition to its well-known immune functions, B7-H3 exhibits dual co-stimulatory/co-inhibitory roles in normal physiology and the tumor microenvironment. The non-immune functions of B7-H3 in tumor cells and the tumor vasculature, including promoting tumor cell anti-apoptosis, proliferation, invasion, migration, drug resistance, radioresistance, as well as affecting cellular metabolism and angiogenesis, have increasingly gained attention from researchers. Particularly, the co-expression of B7-H3 in both tumor cells and tumor endothelial cells highlights the higher potential and clinical utility of therapeutic strategies targeting B7-H3. This review aims to summarize the recent advances in understanding the non-immune functions of B7-H3 in tumors and provide insights into therapeutic approaches targeting B7-H3, focusing on its co-expression in tumor cells and endothelial cells. The aim is to establish a theoretical foundation and practical reference for the development and optimization of B7-H3-targeted therapies.
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Affiliation(s)
- Shuo Wu
- Department of Oncology, Lianyungang Clinical College of Nanjing Medical University, Lianyungang, China
| | - Chenxi Hu
- Department of Oncology, The Affiliated Lianyungang Hospital of Xuzhou Medical University, Lianyungang, China
| | - Kaiyuan Hui
- Department of Oncology, The Affiliated Lianyungang Hospital of Xuzhou Medical University, Lianyungang, China
| | - Xiaodong Jiang
- Department of Oncology, Lianyungang Clinical College of Nanjing Medical University, Lianyungang, China
- Department of Oncology, The Affiliated Lianyungang Hospital of Xuzhou Medical University, Lianyungang, China
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Wu J, Wang C, Cui X, Liu L, Wang L, Wang J, Xue X, Dang T. MicroRNA-128 acts as a suppressor in the progression of gastrointestinal stromal tumor by targeting B-lymphoma Mo-MLV insertion region 1. Clin Transl Oncol 2024; 26:363-374. [PMID: 38103120 DOI: 10.1007/s12094-023-03354-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Accepted: 01/11/2023] [Indexed: 12/17/2023]
Abstract
INTRODUCTION The critical role of microRNA-128 (miR-128) in gastrointestinal-related diseases has been documented. In the current study, we tried to clarify the specific role miR-128 in gastrointestinal stromal tumor (GIST) and the underlying mechanism. METHODS Differentially expressed genes in GIST were identified following bioinformatics analysis. Then, expression patterns of miR-128 and B-lymphoma Mo-MLV insertion region 1 (BMI-1) in clinical tissue samples and cell lines were characterized, followed by validation of their correlation. GIST-T1 cells were selected and transfected with different mimic, inhibitor, or siRNA plasmids, after which the biological functions were assayed. RESULTS We identified low miR-128 and high BMI-1 expression in GIST tissues of 78 patients and 4 GIST cell lines. Ectopic expression of miR-128 or silencing of BMI-1 suppressed the malignant potentials of GIST-T1 cells. As a target of miR-128, BMI-1 re-expression could partly counteract the suppressive effect of miR-128 on the malignancy of GIST-T1 cells. CONCLUSION Our study provided evidence that miR-128-mediated silencing of BMI-1 could prevent malignant progression of GIST, highlighting a promising anti-tumor target for combating GIST.
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Affiliation(s)
- Jinbao Wu
- Inner Mongolia Institute of Digestive Diseases, The Second Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, No. 30, Hudemulin Street, Qingshan District, Baotou, 014030, Inner Mongolia Autonomous Region, People's Republic of China
| | - Changjuan Wang
- Inner Mongolia Institute of Digestive Diseases, The Second Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, No. 30, Hudemulin Street, Qingshan District, Baotou, 014030, Inner Mongolia Autonomous Region, People's Republic of China
| | - Xia Cui
- Inner Mongolia Institute of Digestive Diseases, The Second Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, No. 30, Hudemulin Street, Qingshan District, Baotou, 014030, Inner Mongolia Autonomous Region, People's Republic of China
| | - Lin Liu
- Inner Mongolia Institute of Digestive Diseases, The Second Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, No. 30, Hudemulin Street, Qingshan District, Baotou, 014030, Inner Mongolia Autonomous Region, People's Republic of China
| | - Lu Wang
- Inner Mongolia Institute of Digestive Diseases, The Second Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, No. 30, Hudemulin Street, Qingshan District, Baotou, 014030, Inner Mongolia Autonomous Region, People's Republic of China
| | - Jing Wang
- Inner Mongolia Institute of Digestive Diseases, The Second Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, No. 30, Hudemulin Street, Qingshan District, Baotou, 014030, Inner Mongolia Autonomous Region, People's Republic of China
| | - Xiaohui Xue
- Inner Mongolia Institute of Digestive Diseases, The Second Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, No. 30, Hudemulin Street, Qingshan District, Baotou, 014030, Inner Mongolia Autonomous Region, People's Republic of China
| | - Tong Dang
- Inner Mongolia Institute of Digestive Diseases, The Second Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, No. 30, Hudemulin Street, Qingshan District, Baotou, 014030, Inner Mongolia Autonomous Region, People's Republic of China.
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Effer B, Perez I, Ulloa D, Mayer C, Muñoz F, Bustos D, Rojas C, Manterola C, Vergara-Gómez L, Dappolonnio C, Weber H, Leal P. Therapeutic Targets of Monoclonal Antibodies Used in the Treatment of Cancer: Current and Emerging. Biomedicines 2023; 11:2086. [PMID: 37509725 PMCID: PMC10377242 DOI: 10.3390/biomedicines11072086] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 07/14/2023] [Accepted: 07/17/2023] [Indexed: 07/30/2023] Open
Abstract
Cancer is one of the leading global causes of death and disease, and treatment options are constantly evolving. In this sense, the use of monoclonal antibodies (mAbs) in immunotherapy has been considered a fundamental aspect of modern cancer therapy. In order to avoid collateral damage, it is indispensable to identify specific molecular targets or biomarkers of therapy and/or diagnosis (theragnostic) when designing an appropriate immunotherapeutic regimen for any type of cancer. Furthermore, it is important to understand the currently employed mAbs in immunotherapy and their mechanisms of action in combating cancer. To achieve this, a comprehensive understanding of the biology of cancer cell antigens, domains, and functions is necessary, including both those presently utilized and those emerging as potential targets for the design of new mAbs in cancer treatment. This review aims to provide a description of the therapeutic targets utilized in cancer immunotherapy over the past 5 years, as well as emerging targets that hold promise as potential therapeutic options in the application of mAbs for immunotherapy. Additionally, the review explores the mechanisms of actin of the currently employed mAbs in immunotherapy.
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Affiliation(s)
- Brian Effer
- Center of Excellence in Translational Medicine (CEMT) and Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco 4811230, Chile
| | - Isabela Perez
- Center of Excellence in Translational Medicine (CEMT) and Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco 4811230, Chile
| | - Daniel Ulloa
- Center of Excellence in Translational Medicine (CEMT) and Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco 4811230, Chile
| | - Carolyn Mayer
- Center of Excellence in Translational Medicine (CEMT) and Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco 4811230, Chile
| | - Francisca Muñoz
- Center of Excellence in Translational Medicine (CEMT) and Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco 4811230, Chile
| | - Diego Bustos
- Center of Excellence in Translational Medicine (CEMT) and Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco 4811230, Chile
| | - Claudio Rojas
- Programa de Doctorado en Ciencias Médicas, Universidad de la Frontera, Temuco 4811230, Chile
- Centro de Estudios Morfológicos y Quirúrgicos de La, Universidad de La Frontera, Temuco 4811230, Chile
| | - Carlos Manterola
- Programa de Doctorado en Ciencias Médicas, Universidad de la Frontera, Temuco 4811230, Chile
- Centro de Estudios Morfológicos y Quirúrgicos de La, Universidad de La Frontera, Temuco 4811230, Chile
| | - Luis Vergara-Gómez
- Center of Excellence in Translational Medicine (CEMT) and Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco 4811230, Chile
| | - Camila Dappolonnio
- Center of Excellence in Translational Medicine (CEMT) and Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco 4811230, Chile
| | - Helga Weber
- Center of Excellence in Translational Medicine (CEMT) and Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco 4811230, Chile
| | - Pamela Leal
- Center of Excellence in Translational Medicine (CEMT) and Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco 4811230, Chile
- Department of Agricultural Sciences and Natural Resources, Faculty of Agricultural and Forestry Science, Universidad de La Frontera, Temuco 4810296, Chile
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15
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Liu HJ, Du H, Khabibullin D, Zarei M, Wei K, Freeman GJ, Kwiatkowski DJ, Henske EP. mTORC1 upregulates B7-H3/CD276 to inhibit antitumor T cells and drive tumor immune evasion. Nat Commun 2023; 14:1214. [PMID: 36869048 PMCID: PMC9984496 DOI: 10.1038/s41467-023-36881-7] [Citation(s) in RCA: 38] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Accepted: 02/21/2023] [Indexed: 03/05/2023] Open
Abstract
Identifying the mechanisms underlying the regulation of immune checkpoint molecules and the therapeutic impact of targeting them in cancer is critical. Here we show that high expression of the immune checkpoint B7-H3 (CD276) and high mTORC1 activity correlate with immunosuppressive phenotypes and worse clinical outcomes in 11,060 TCGA human tumors. We find that mTORC1 upregulates B7-H3 expression via direct phosphorylation of the transcription factor YY2 by p70 S6 kinase. Inhibition of B7-H3 suppresses mTORC1-hyperactive tumor growth via an immune-mediated mechanism involving increased T-cell activity and IFN-γ responses coupled with increased tumor cell expression of MHC-II. CITE-seq reveals strikingly increased cytotoxic CD38+CD39+CD4+ T cells in B7-H3-deficient tumors. In pan-human cancers, a high cytotoxic CD38+CD39+CD4+ T-cell gene signature correlates with better clinical prognosis. These results show that mTORC1-hyperactivity, present in many human tumors including tuberous sclerosis complex (TSC) and lymphangioleiomyomatosis (LAM), drives B7-H3 expression leading to suppression of cytotoxic CD4+ T cells.
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Affiliation(s)
- Heng-Jia Liu
- Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, 02115, MA, USA.
| | - Heng Du
- Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, 02115, MA, USA
| | - Damir Khabibullin
- Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, 02115, MA, USA
| | - Mahsa Zarei
- Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, 02115, MA, USA
- Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, 77843, TX, USA
| | - Kevin Wei
- Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital and Harvard Medical School, Boston, 02115, MA, USA
| | - Gordon J Freeman
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, 02215, MA, USA
| | - David J Kwiatkowski
- Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, 02115, MA, USA
| | - Elizabeth P Henske
- Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, 02115, MA, USA.
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16
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Getu AA, Tigabu A, Zhou M, Lu J, Fodstad Ø, Tan M. New frontiers in immune checkpoint B7-H3 (CD276) research and drug development. Mol Cancer 2023; 22:43. [PMID: 36859240 PMCID: PMC9979440 DOI: 10.1186/s12943-023-01751-9] [Citation(s) in RCA: 94] [Impact Index Per Article: 47.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Accepted: 02/22/2023] [Indexed: 03/03/2023] Open
Abstract
B7-H3 (CD276), a member of the B7 family of proteins, is a key player in cancer progression. This immune checkpoint molecule is selectively expressed in both tumor cells and immune cells within the tumor microenvironment. In addition to its immune checkpoint function, B7-H3 has been linked to tumor cell proliferation, metastasis, and therapeutic resistance. Furthermore, its drastic difference in protein expression levels between normal and tumor tissues suggests that targeting B7-H3 with drugs would lead to cancer-specific toxicity, minimizing harm to healthy cells. These properties make B7-H3 a promising target for cancer therapy.Recently, important advances in B7-H3 research and drug development have been reported, and these new findings, including its involvement in cellular metabolic reprograming, cancer stem cell enrichment, senescence and obesity, have expanded our knowledge and understanding of this molecule, which is important in guiding future strategies for targeting B7-H3. In this review, we briefly discuss the biology and function of B7-H3 in cancer development. We emphasize more on the latest findings and their underlying mechanisms to reflect the new advances in B7-H3 research. In addition, we discuss the new improvements of B-H3 inhibitors in cancer drug development.
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Affiliation(s)
- Ayechew Adera Getu
- Institute of Biochemistry and Molecular Biology, Institute of Biomedical Sciences, and Research Center for Cancer Biology, China Medical University, Taichung, Taiwan
- Department of Physiology, School of Medicine, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Abiye Tigabu
- Institute of Biochemistry and Molecular Biology, Institute of Biomedical Sciences, and Research Center for Cancer Biology, China Medical University, Taichung, Taiwan
| | - Ming Zhou
- Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha, China
| | - Jianrong Lu
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, USA
| | - Øystein Fodstad
- Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway
| | - Ming Tan
- Institute of Biochemistry and Molecular Biology, Institute of Biomedical Sciences, and Research Center for Cancer Biology, China Medical University, Taichung, Taiwan.
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17
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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: 91] [Impact Index Per Article: 30.3] [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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Yu C, Zhou Z, Huang W, Li X, Zou F, Meng X, Cai S. Orai3 mediates Orai channel remodelling to activate fibroblast in pulmonary fibrosis. J Cell Mol Med 2022; 26:4974-4985. [PMID: 36128650 PMCID: PMC9549502 DOI: 10.1111/jcmm.17516] [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: 08/14/2021] [Revised: 04/23/2022] [Accepted: 06/21/2022] [Indexed: 11/30/2022] Open
Abstract
Orai family are a calcium channel of cell membrane extracellular Ca2+ influx which participates in tissue fibrosis. But the roles of Orai3 have less attention on the mechanism of regulating lung fibrosis. In this study, we found that Orai3 expression was increased significantly in BLM‐induced lung fibrosis. The knockdown of Orai3 decreased TGF‐β1‐induced fibroblast proliferation, ECM production, activation of NFAT1 and Calpain/ERK signal pathway and glycolysis levels. Orai3 interacting with Orai1 was increased in BLM‐induced lung fibrosis and TGF‐β1‐induced fibroblast, while the Stim1 interacting with Orai1 and SOCE activity was suppressed, leading in a high and stable extracellular Ca2+ influx. Furthermore, the over‐expression of Orai3 did not enhance Orai3 interacting with Orai1 under TGF‐β1 free fibroblast. And then, the deeper mechanism of TGF‐β1‐induced increased SEPTIN4 promoted Orai3 interacting with Orai1. Our results indicated that Orai3 could be one of the therapy targets for PF in which remodels Orai channel, suppresses SOCE activity and activated fibroblast to alleviate fibrosis progress.
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Affiliation(s)
- Changhui Yu
- Chronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Zicong Zhou
- Chronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Wufeng Huang
- Chronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiumei Li
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Fei Zou
- Guangdong Provincial Key Laboratory of Tropical Disease Research, Department of Occupational Health and Occupational Medicine, School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou, China
| | - Xiaojing Meng
- Guangdong Provincial Key Laboratory of Tropical Disease Research, Department of Occupational Health and Occupational Medicine, School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou, China
| | - Shaoxi Cai
- Chronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China
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The Features of Immune Checkpoint Gene Regulation by microRNA in Cancer. Int J Mol Sci 2022; 23:ijms23169324. [PMID: 36012588 PMCID: PMC9409052 DOI: 10.3390/ijms23169324] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 08/15/2022] [Accepted: 08/16/2022] [Indexed: 02/06/2023] Open
Abstract
Currently, the search for new promising tools of immunotherapy continues. In this regard, microRNAs (miRNAs) that influence immune checkpoint (IC) gene expression in tumor and T-cells and may be important regulators of immune cells are considered. MiRNAs regulate gene expression by blocking mRNA translation. An important feature of miRNA is its ability to affect the expression of several genes simultaneously, which corresponds to the trend toward the use of combination therapy. The article provides a list of miRNAs acting simultaneously on several ICs and miRNAs that, in addition to IC, can regulate the expression of targeted therapy genes. There is dependence of miRNA interactions with IC genes on the type of cancer. The analysis of the accumulated data demonstrates that only about 14% (95% CI: 9.8–20.1%) of the studied miRNAs regulate the expression of specific IC in more than one type of cancer. That is, there is tumor specificity in the miRNA action on ICs. A number of miRNAs demonstrated high efficiency in vitro and in vivo. This indicates the potential of miRNAs as promising agents for cancer immunotherapy. Additional studies of the miRNA–gene interaction features and the search for an optimal miRNA mimic structure are necessary.
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20
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Clinical significance of B7-H3 and HER2 co-expression and therapeutic value of combination treatment in gastric cancer. Int Immunopharmacol 2022; 110:108988. [PMID: 35777267 DOI: 10.1016/j.intimp.2022.108988] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 06/13/2022] [Accepted: 06/19/2022] [Indexed: 11/22/2022]
Abstract
BACKGROUND Gastric cancer (GC) is a digestive system malignancy. Trastuzumab (a HER2-targeted monoclonal antibody) is an important targeted drug for GC. However, the drug resistance limits its clinical efficacy. B7-H3 was suggested to be a promising target for cancer immunotherapy. This study aimed to investigate the clinical significance of B7-H3 and HER2 co-expression and the therapeutic value of combination treatment in GC. METHODS We examined the expression of B7-H3 and HER2 in 268 GC patients by immunohistochemistry. Pearson test was used to analyze the correlation between categorical variables. Overall survival was assessed by Kaplan-Meier analysis. All in vitro experiments using HER2-positive GC cells were treated with small interfering RNA targeting B7-H3/HER2 or B7-H3 blocking antibody 3E8/trastuzumab to verify the antitumor efficacy of the combination therapy. GC xenograft mouse models were established to evaluate the in vivo anti-tumor effect of combined therapy. RESULTS There was a significant correlation between B7-H3 and HER2 expression in GC tissues. High co-expression of B7-H3 and HER2 was associated with poor prognosis (P = 0.007) and could be an independent risk factor for survival. In addition, knockdown or targeted therapies of B7-H3/HER2 significantly suppressed cell proliferation, migration, invasion and adhesion in vitro. Trastuzumab combined with 3E8 was significantly effective at reducing mice tumor growth than monotherapy. CONCLUSION High co-expression of B7-H3 and HER2 indicates a poor prognosis, and combination therapy targeting B7-H3 and HER2 could be an immunotherapeutic strategy for GC.
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Zhou WT, Jin WL. B7-H3/CD276: An Emerging Cancer Immunotherapy. Front Immunol 2021; 12:701006. [PMID: 34349762 PMCID: PMC8326801 DOI: 10.3389/fimmu.2021.701006] [Citation(s) in RCA: 146] [Impact Index Per Article: 36.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 07/05/2021] [Indexed: 12/18/2022] Open
Abstract
Immunotherapy aiming at suppressing tumor development by relying on modifying or strengthening the immune system prevails among cancer treatments and points out a new direction for cancer therapy. B7 homolog 3 protein (B7-H3, also known as CD276), a newly identified immunoregulatory protein member of the B7 family, is an attractive and promising target for cancer immunotherapy because it is overexpressed in tumor tissues while showing limited expression in normal tissues and participating in tumor microenvironment (TME) shaping and development. Thus far, numerous B7-H3-based immunotherapy strategies have demonstrated potent antitumor activity and acceptable safety profiles in preclinical models. Herein, we present the expression and biological function of B7-H3 in distinct cancer and normal cells, as well as B7-H3-mediated signal pathways in cancer cells and B7-H3-based tumor immunotherapy strategies. This review provides a comprehensive overview that encompasses B7-H3’s role in TME to its potential as a target in cancer immunotherapy.
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Affiliation(s)
- Wu-Tong Zhou
- Institute of Nano Biomedicine and Engineering, Shanghai Engineering Center for Intelligent Diagnosis and Treatment Instrument, Department of Instrument Science and Engineering, Key Laboratory for Thin Film and Microfabrication Technology of Ministry of Education, School of Electronic Information and Electronic Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Wei-Lin Jin
- Institute of Nano Biomedicine and Engineering, Shanghai Engineering Center for Intelligent Diagnosis and Treatment Instrument, Department of Instrument Science and Engineering, Key Laboratory for Thin Film and Microfabrication Technology of Ministry of Education, School of Electronic Information and Electronic Engineering, Shanghai Jiao Tong University, Shanghai, China.,Institute of Cancer Neuroscience, Medical Frontier Innovation Research Center, The First Hospital of Lanzhou University, The First Clinical Medical College of Lanzhou University, Lanzhou, China
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