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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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2
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Duan L, Ma Y, Reisch B, Hadrovic E, Mach P, Kimmig R, Jahn M, Köninger A, Iannaccone A, Gellhaus A. Alteration in sB7-H4 Serum Levels and Placental Biomarker Expression after Therapeutic Plasma Exchange in Early-Onset Preeclampsia Patients. Int J Mol Sci 2024; 25:11082. [PMID: 39456867 PMCID: PMC11507903 DOI: 10.3390/ijms252011082] [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: 09/17/2024] [Revised: 10/12/2024] [Accepted: 10/12/2024] [Indexed: 10/28/2024] Open
Abstract
Therapeutic plasma exchange (TPE) is a widely used treatment for numerous diseases including pregnancy-related conditions. Our prior study on 20 early-onset preeclampsia patients undergoing TPE revealed a significant extension in pregnancy duration and reduced serum levels of sFlt-1, sFlt-1/PlGF, and sEndoglin. Here, we investigated the impact of TPE on serum sB7-H4, an immunological checkpoint molecule, and placental proteins (Flt-1, Eng, B7-H4, iNOS, TNF-α) in TPE-treated early-onset preeclampsia patients (N = 12, 23 + 2-28 + 5 weeks), conventionally treated counterparts (N = 12, 23 + 5-30 weeks), and gestational age-matched controls (N = 8, 22 + 4-31 + 6 weeks). Immunoblotting, ELISA, and co-immunohistochemistry were used for biomarker analysis, including placental inflammation factors (iNOS, TNF-α). The results showed that TPE extended pregnancy by a median of 6.5 days in this cohort of early-onset preeclampsia. Serum sB7-H4, sFlt-1, and sEndoglin levels decreased, along with reduced expression of their membrane-bound proteins in placental tissue upon TPE treatment. Moreover, TPE-treated patients displayed reduced placental inflammation compared to preeclampsia patients receiving standard-of-care treatment. In conclusion, TPE may improve pregnancy outcomes in early-onset preeclampsia by lowering circulating levels of sB7-H4, sFlt-1, and sEndoglin, as well as reducing placental inflammation. This translational approach holds promise for enhancing placental function and extending gestation in high-risk pregnancies including very preterm PE or HELLP cases.
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Affiliation(s)
- Liyan Duan
- Department of Gynecology and Obstetrics, University of Duisburg-Essen, 45147 Essen, Germany; (L.D.); (Y.M.); (B.R.); (E.H.); (P.M.); (R.K.); (A.K.)
| | - Yuyang Ma
- Department of Gynecology and Obstetrics, University of Duisburg-Essen, 45147 Essen, Germany; (L.D.); (Y.M.); (B.R.); (E.H.); (P.M.); (R.K.); (A.K.)
| | - Beatrix Reisch
- Department of Gynecology and Obstetrics, University of Duisburg-Essen, 45147 Essen, Germany; (L.D.); (Y.M.); (B.R.); (E.H.); (P.M.); (R.K.); (A.K.)
| | - Elina Hadrovic
- Department of Gynecology and Obstetrics, University of Duisburg-Essen, 45147 Essen, Germany; (L.D.); (Y.M.); (B.R.); (E.H.); (P.M.); (R.K.); (A.K.)
| | - Pawel Mach
- Department of Gynecology and Obstetrics, University of Duisburg-Essen, 45147 Essen, Germany; (L.D.); (Y.M.); (B.R.); (E.H.); (P.M.); (R.K.); (A.K.)
| | - Rainer Kimmig
- Department of Gynecology and Obstetrics, University of Duisburg-Essen, 45147 Essen, Germany; (L.D.); (Y.M.); (B.R.); (E.H.); (P.M.); (R.K.); (A.K.)
| | - Michael Jahn
- Department of Nephrology, University of Duisburg-Essen, University Hospital Essen, 45147 Essen, Germany;
| | - Angela Köninger
- Department of Gynecology and Obstetrics, University of Duisburg-Essen, 45147 Essen, Germany; (L.D.); (Y.M.); (B.R.); (E.H.); (P.M.); (R.K.); (A.K.)
- Department of Gynecology and Obstetrics, University Clinic St. Hedwig of the Order of St. John, 93049 Regensburg, Germany
| | - Antonella Iannaccone
- Department of Gynecology and Obstetrics, University of Duisburg-Essen, 45147 Essen, Germany; (L.D.); (Y.M.); (B.R.); (E.H.); (P.M.); (R.K.); (A.K.)
| | - Alexandra Gellhaus
- Department of Gynecology and Obstetrics, University of Duisburg-Essen, 45147 Essen, Germany; (L.D.); (Y.M.); (B.R.); (E.H.); (P.M.); (R.K.); (A.K.)
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Zhou L, Duan Y, Fu K, Zhang M, Li K, Yin R. The role of B7-H4 in ovarian cancer immunotherapy: current status, challenges, and perspectives. Front Immunol 2024; 15:1426050. [PMID: 39267740 PMCID: PMC11390377 DOI: 10.3389/fimmu.2024.1426050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Accepted: 08/13/2024] [Indexed: 09/15/2024] Open
Abstract
Immunotherapy stands as a critical and auspicious therapeutic approach in the fight against cancer nowadays. Immune checkpoint inhibitors, in particular, have garnered widespread employment and delivered groundbreaking therapeutic outcomes across various malignancies. However, the efficacy is unsatisfactory in the ovarian cancer. The pressing concerns of the substantial non-response rate require immediate attention. The pursuit of novel targets and the formulation of synergistic combination therapy approaches are imperative for addressing this challenge. B7-H4, a member of the B7 family of co-inhibitory molecules, exhibits high expression levels in ovarian cancer, correlating closely with tumor progression, drug resistance, and unfavorable prognosis. B7-H4 has the potential to serve as a valuable biomarker for evaluating the immune response of patients. Recent investigations and preclinical trials focusing on B7-H4 in the context of ovarian cancer immunotherapy highlight its emergence as a promising immunotherapeutic target. This review aims to discuss these findings and anticipate the future prospects of leveraging B7-H4 in ovarian cancer immunotherapy and targeted therapy.
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Affiliation(s)
- Lu Zhou
- Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Yuanqiong Duan
- Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Kaiyu Fu
- Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Mengpei Zhang
- Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Kemin Li
- Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Rutie Yin
- Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, China
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Dawidowicz M, Kot A, Mielcarska S, Psykała K, Kula A, Waniczek D, Świętochowska E. B7H4 Role in Solid Cancers: A Review of the Literature. Cancers (Basel) 2024; 16:2519. [PMID: 39061159 PMCID: PMC11275172 DOI: 10.3390/cancers16142519] [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: 06/03/2024] [Revised: 06/27/2024] [Accepted: 07/09/2024] [Indexed: 07/28/2024] Open
Abstract
Anti-cancer immunotherapies entirely changed the therapeutic approach to oncological patients. However, despite the undeniable success of anti-PD-1, PD-L1, and CTLA-4 antibody treatments, their effectiveness is limited either by certain types of malignancies or by the arising problem of cancer resistance. B7H4 (aliases B7x, B7H4, B7S1, VTCN1) is a member of a B7 immune checkpoint family with a distinct expression pattern from classical immune checkpoint pathways. The growing amount of research results seem to support the thesis that B7H4 might be a very potent therapeutic target. B7H4 was demonstrated to promote tumour progression in immune "cold" tumours by promoting migration, proliferation of tumour cells, and cancer stem cell persistence. B7H4 suppresses T cell effector functions, including inflammatory cytokine production, cytolytic activity, proliferation of T cells, and promoting the polarisation of naïve CD4 T cells into induced Tregs. This review aimed to summarise the available information about B7H4, focusing in particular on clinical implications, immunological mechanisms, potential strategies for malignancy treatment, and ongoing clinical trials.
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Affiliation(s)
- Miriam Dawidowicz
- Department of Oncological Surgery, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 41-808 Katowice, Poland
| | - Anna Kot
- Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 19 Jordana, 41-800 Zabrze, Poland
| | - Sylwia Mielcarska
- Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 19 Jordana, 41-800 Zabrze, Poland
| | - Katarzyna Psykała
- Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 19 Jordana, 41-800 Zabrze, Poland
| | - Agnieszka Kula
- Department of Oncological Surgery, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 41-808 Katowice, Poland
| | - Dariusz Waniczek
- Department of Oncological Surgery, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 41-808 Katowice, Poland
| | - Elżbieta Świętochowska
- Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 19 Jordana, 41-800 Zabrze, Poland
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Wescott EC, Sun X, Gonzalez-Ericsson P, Hanna A, Taylor BC, Sanchez V, Bronzini J, Opalenik SR, Sanders ME, Wulfkuhle J, Gallagher RI, Gomez H, Isaacs C, Bharti V, Wilson JT, Ballinger TJ, Santa-Maria CA, Shah PD, Dees EC, Lehmann BD, Abramson VG, Hirst GL, Brown Swigart L, van ˈt Veer LJ, Esserman LJ, Petricoin EF, Pietenpol JA, Balko JM. Epithelial Expressed B7-H4 Drives Differential Immunotherapy Response in Murine and Human Breast Cancer. CANCER RESEARCH COMMUNICATIONS 2024; 4:1120-1134. [PMID: 38687247 PMCID: PMC11041871 DOI: 10.1158/2767-9764.crc-23-0468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Revised: 01/30/2024] [Accepted: 03/29/2024] [Indexed: 05/02/2024]
Abstract
Combinations of immune checkpoint inhibitors (ICI, including anti-PD-1/PD-L1) and chemotherapy have been FDA approved for metastatic and early-stage triple-negative breast cancer (TNBC), but most patients do not benefit. B7-H4 is a B7 family ligand with proposed immunosuppressive functions being explored as a cancer immunotherapy target and may be associated with anti-PD-L1 resistance. However, little is known about its regulation and effect on immune cell function in breast cancers. We assessed murine and human breast cancer cells to identify regulation mechanisms of B7-H4 in vitro. We used an immunocompetent anti-PD-L1-sensitive orthotopic mammary cancer model and induced ectopic expression of B7-H4. We assessed therapy response and transcriptional changes at baseline and under treatment with anti-PD-L1. We observed B7-H4 was highly associated with epithelial cell status and transcription factors and found to be regulated by PI3K activity. EMT6 tumors with cell-surface B7-H4 expression were more resistant to immunotherapy. In addition, tumor-infiltrating immune cells had reduced immune activation signaling based on transcriptomic analysis. Paradoxically, in human breast cancer, B7-H4 expression was associated with survival benefit for patients with metastatic TNBC treated with carboplatin plus anti-PD-L1 and was associated with no change in response or survival for patients with early breast cancer receiving chemotherapy plus anti-PD-1. While B7-H4 induces tumor resistance to anti-PD-L1 in murine models, there are alternative mechanisms of signaling and function in human cancers. In addition, the strong correlation of B7-H4 to epithelial cell markers suggests a potential regulatory mechanism of B7-H4 independent of PD-L1. SIGNIFICANCE This translational study confirms the association of B7-H4 expression with a cold immune microenvironment in breast cancer and offers preclinical studies demonstrating a potential role for B7-H4 in suppressing response to checkpoint therapy. However, analysis of two clinical trials with checkpoint inhibitors in the early and metastatic settings argue against B7-H4 as being a mechanism of clinical resistance to checkpoints, with clear implications for its candidacy as a therapeutic target.
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Affiliation(s)
- Elizabeth C. Wescott
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Xiaopeng Sun
- Breast Cancer Research Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Paula Gonzalez-Ericsson
- Breast Cancer Research Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Ann Hanna
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Brandie C. Taylor
- Breast Cancer Research Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Violeta Sanchez
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Juliana Bronzini
- Department of Biological Sciences, Vanderbilt University, Nashville, Tennessee
| | - Susan R. Opalenik
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Melinda E. Sanders
- Breast Cancer Research Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Julia Wulfkuhle
- Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, Virginia
| | - Rosa I. Gallagher
- Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, Virginia
| | - Henry Gomez
- Department of Medical Oncology, Instituto Nacional de Enfermedades Neoplásicas, Lima, Perú
| | - Claudine Isaacs
- Division of Hematology-Oncology, Department of Medicine, Georgetown University, Washington, District of Columbia
| | - Vijaya Bharti
- Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, Tennessee
| | - John T. Wilson
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee
- Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, Tennessee
| | - Tarah J. Ballinger
- Division of Hematology and Oncology, Indiana University School of Medicine, Indianapolis, Indiana
| | | | - Payal D. Shah
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Elizabeth C. Dees
- Department of Medicine, School of Medicine, University of North Carolina, Chapel Hill, North Carolina
| | - Brian D. Lehmann
- Breast Cancer Research Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Vandana G. Abramson
- Breast Cancer Research Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Gillian L. Hirst
- Department of Surgery, University of California San Francisco, San Francisco, California
| | - Lamorna Brown Swigart
- Department of Laboratory Medicine, University of California San Francisco, San Francisco, California
| | - Laura J. van ˈt Veer
- Department of Laboratory Medicine, University of California San Francisco, San Francisco, California
| | - Laura J. Esserman
- Department of Surgery, University of California San Francisco, San Francisco, California
| | - Emanuel F. Petricoin
- Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, Virginia
| | - Jennifer A. Pietenpol
- Breast Cancer Research Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
- Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland
- Department of Biochemistry, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Justin M. Balko
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee
- Breast Cancer Research Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
- Cancer Biology Program, Vanderbilt University, Nashville, Tennessee
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Siqueira JM, Mitani Y, Hoff CO, Bonini F, Guimaraes de Sousa L, Marques-Piubelli ML, Purushothaman A, Mitani M, Dai H, Lin SY, Spiotto MT, Hanna EY, McGrail DJ, El-Naggar AK, Ferrarotto R. Analysis of B7-H4 Expression Across Salivary Gland Carcinomas Reveals Adenoid Cystic Carcinoma-Specific Prognostic Relevance. Mod Pathol 2024; 37:100371. [PMID: 38015043 DOI: 10.1016/j.modpat.2023.100371] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Revised: 10/11/2023] [Accepted: 10/22/2023] [Indexed: 11/29/2023]
Abstract
B7-H4 (VTCN1), a member of the B7 family, is overexpressed in several types of cancer. Here we investigated the pattern of expression of B7-H4 in salivary gland carcinomas (SGC) and assessed its potential as a prognostic marker and therapeutic target. Immunohistochemistry (IHC) analyses were performed in a cohort of 340 patient tumors, composed of 124 adenoid cystic carcinomas (ACC), 107 salivary duct carcinomas (SDC), 64 acinic cell carcinomas, 36 mucoepidermoid carcinomas (MEC), 9 secretory carcinomas (SC), as well as 20 normal salivary glands (controls). B7-H4 expression was scored and categorized into negative (<5% expression of any intensity), low (5%-70% expression of any intensity or >70% with weak intensity), or high (>70% moderate or strong diffuse intensity). The associations between B7-H4 expression and clinicopathologic characteristics, as well as overall survival, were assessed. Among all tumors, B7-H4 expression was more prevalent in ACC (94%) compared with those of SC (67%), MEC (44%), SDC (32%), and acinic cell carcinomas (0%). Normal salivary gland tissue did not express B7-H4. High expression of B7-H4 was found exclusively in ACC (27%), SDC (11%), and MEC (8%). In SDC, B7-H4 expression was associated with female gender (P = .002) and lack of androgen receptor expression (P = .012). In ACC, B7-H4 expression was significantly associated with solid histology (P < .0001) and minor salivary gland primary (P = .02). High B7-H4 expression was associated with a poorer prognosis in ACC, regardless of clinical stage and histologic subtype. B7-H4 expression was not prognostic in the non-ACC SGC evaluated. Our comparative study revealed distinct patterns of B7-H4 expression according to SGC histology, which has potential therapeutic implications. B7-H4 expression was particularly high in solid ACC and was an independent prognostic marker in this disease but not in the other SGC assessed.
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Affiliation(s)
- Juliana Mota Siqueira
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Stomatology, Discipline of Oral and Maxillofacial Pathology, School of Dentistry, University of São Paulo, São Paulo, SP, Brazil
| | - Yoshitsugu Mitani
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Camilla Oliveira Hoff
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Flavia Bonini
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Luana Guimaraes de Sousa
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Mario L Marques-Piubelli
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Anurag Purushothaman
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Mutsumi Mitani
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Hui Dai
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Shiaw-Yih Lin
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Michael T Spiotto
- Department of Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Ehab Y Hanna
- Department of Head and Neck Surgery, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Daniel J McGrail
- Center for Immunotherapy and Precision Immuno-Oncology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio
| | - Adel K El-Naggar
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Renata Ferrarotto
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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7
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Xiao L, Guan X, Xiang M, Wang Q, Long Q, Yue C, Chen L, Liu J, Liao C. B7 family protein glycosylation: Promising novel targets in tumor treatment. Front Immunol 2022; 13:1088560. [PMID: 36561746 PMCID: PMC9763287 DOI: 10.3389/fimmu.2022.1088560] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Accepted: 11/22/2022] [Indexed: 12/12/2022] Open
Abstract
Cancer immunotherapy, including the inhibition of immune checkpoints, improves the tumor immune microenvironment and is an effective tool for cancer therapy. More effective and alternative inhibitory targets are critical for successful immune checkpoint blockade therapy. The interaction of the immunomodulatory ligand B7 family with corresponding receptors induces or inhibits T cell responses by sending co-stimulatory and co-inhibitory signals respectively. Blocking the glycosylation of the B7 family members PD-L1, PD-L2, B7-H3, and B7-H4 inhibited the self-stability and receptor binding of these immune checkpoint proteins, leading to immunosuppression and rapid tumor progression. Therefore, regulation of glycosylation may be the "golden key" to relieve tumor immunosuppression. The exploration of a more precise glycosylation regulation mechanism and glycan structure of B7 family proteins is conducive to the discovery and clinical application of antibodies and small molecule inhibitors.
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Affiliation(s)
- Linlin Xiao
- Department of Orthodontics II, Affiliated Stomatological Hospital of Zunyi Medical University, Zunyi, China,Oral Disease Research Key Laboratory of Guizhou Tertiary Institution, School of Stomatology, Zunyi Medical University, Zunyi, China
| | - Xiaoyan Guan
- Department of Orthodontics II, Affiliated Stomatological Hospital of Zunyi Medical University, Zunyi, China,Oral Disease Research Key Laboratory of Guizhou Tertiary Institution, School of Stomatology, Zunyi Medical University, Zunyi, China
| | - Mingli Xiang
- Department of Orthodontics II, Affiliated Stomatological Hospital of Zunyi Medical University, Zunyi, China,Oral Disease Research Key Laboratory of Guizhou Tertiary Institution, School of Stomatology, Zunyi Medical University, Zunyi, China
| | - Qian Wang
- Oral Disease Research Key Laboratory of Guizhou Tertiary Institution, School of Stomatology, Zunyi Medical University, Zunyi, China
| | - Qian Long
- Department of Orthodontics II, Affiliated Stomatological Hospital of Zunyi Medical University, Zunyi, China,Oral Disease Research Key Laboratory of Guizhou Tertiary Institution, School of Stomatology, Zunyi Medical University, Zunyi, China
| | - Chaoyi Yue
- School of Medicine and Technology, Zunyi Medical University, Zunyi, China
| | - Lulu Chen
- Department of Orthodontics II, Affiliated Stomatological Hospital of Zunyi Medical University, Zunyi, China,Oral Disease Research Key Laboratory of Guizhou Tertiary Institution, School of Stomatology, Zunyi Medical University, Zunyi, China
| | - Jianguo Liu
- Oral Disease Research Key Laboratory of Guizhou Tertiary Institution, School of Stomatology, Zunyi Medical University, Zunyi, China,*Correspondence: Chengcheng Liao, ; Jianguo Liu,
| | - Chengcheng Liao
- Department of Orthodontics II, Affiliated Stomatological Hospital of Zunyi Medical University, Zunyi, China,Oral Disease Research Key Laboratory of Guizhou Tertiary Institution, School of Stomatology, Zunyi Medical University, Zunyi, China,*Correspondence: Chengcheng Liao, ; Jianguo Liu,
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8
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Yang M, Tian S, Lin Z, Fu Z, Li C. Costimulatory and coinhibitory molecules of B7-CD28 family in cardiovascular atherosclerosis: A review. Medicine (Baltimore) 2022; 101:e31667. [PMID: 36397436 PMCID: PMC9666218 DOI: 10.1097/md.0000000000031667] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Accumulating evidence supports the active involvement of vascular inflammation in atherosclerosis pathogenesis. Vascular inflammatory events within atherosclerotic plaques are predominated by innate antigen-presenting cells (APCs), including dendritic cells, macrophages, and adaptive immune cells such as T lymphocytes. The interaction between APCs and T cells is essential for the initiation and progression of vascular inflammation during atherosclerosis formation. B7-CD28 family members that provide either costimulatory or coinhibitory signals to T cells are important mediators of the cross-talk between APCs and T cells. The balance of different functional members of the B7-CD28 family shapes T cell responses during inflammation. Recent studies from both mouse and preclinical models have shown that targeting costimulatory molecules on APCs and T cells may be effective in treating vascular inflammatory diseases, especially atherosclerosis. In this review, we summarize recent advances in understanding how APC and T cells are involved in the pathogenesis of atherosclerosis by focusing on B7-CD28 family members and provide insight into the immunotherapeutic potential of targeting B7-CD28 family members in atherosclerosis.
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Affiliation(s)
- Mao Yang
- Department of Cardiology, Electrophysiological Center of Cardiology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Simeng Tian
- Basic Medicine College, Harbin Medical University, Harbin, China
| | - Zhoujun Lin
- State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, China
| | - Zhenkun Fu
- Basic Medicine College, Harbin Medical University, Harbin, China
- State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, China
- Department of Immunology, Wu Lien-Teh Institute, Heilongjiang Provincial Key Laboratory for Infection and Immunity, Harbin Medical University, Heilongjiang Academy of Medical Science, Harbin, China
- * Correspondence: Zhenkun Fu, Basic Medicine College, Harbin Medical University, Harbin, China (e-mail. ); Chenggang Li, State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, China (e-mail. )
| | - Chenggang Li
- State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, China
- * Correspondence: Zhenkun Fu, Basic Medicine College, Harbin Medical University, Harbin, China (e-mail. ); Chenggang Li, State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, China (e-mail. )
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9
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Vaishnav J, Khan F, Yadav M, Parmar N, Buch H, Jadeja SD, Dwivedi M, Begum R. V-set domain containing T-cell activation inhibitor-1 (VTCN1): A potential target for the treatment of autoimmune diseases. Immunobiology 2022; 227:152274. [PMID: 36095871 DOI: 10.1016/j.imbio.2022.152274] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 08/13/2022] [Accepted: 09/01/2022] [Indexed: 11/23/2022]
Abstract
Autoimmunity eventuates when the immune system attacks self-molecules as a result of the breakdown in immune tolerance. Targeting autoimmune diseases via immunomodulation has become an essential strategy in today's era. A B7 superfamily member immune checkpoint, the V-set domain containing T-cell activation inhibitor-1 (VTCN1), also known as B7-H4, B7S1, and B7x, is involved in negatively regulating T-cell activation. VTCN1 transcript has been reported in various lymphoid and non-lymphoid tissues, but its protein expression is restricted, indicating its translational regulation. Dysregulation of VTCN1 has resulted in the exacerbation of various autoimmune diseases. Moreover, increased soluble form of VTCN1 in the patient's sera positively correlates with the disease progression and severity. The current review summarizes all the reports till date, unfolding the role of VTCN1 in various autoimmune diseases and its therapeutic potential.
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Affiliation(s)
- Jayvadan Vaishnav
- Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara 390002, Gujarat, India
| | - Farheen Khan
- Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara 390002, Gujarat, India
| | - Madhu Yadav
- Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara 390002, Gujarat, India
| | - Nishant Parmar
- Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara 390002, Gujarat, India
| | - Hiteshree Buch
- Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara 390002, Gujarat, India
| | - Shahnawaz D Jadeja
- Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara 390002, Gujarat, India
| | - Mitesh Dwivedi
- Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara 390002, Gujarat, India; C. G. Bhakta Institute of Biotechnology, Uka Tarsadia University, Tarsadi, Surat 394350, Gujarat, India
| | - Rasheedunnisa Begum
- Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara 390002, Gujarat, India.
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10
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Yang W, Huang Q, Han L, Wang B, Yawalkar N, Zhang Z, Yan K. B7-H4 Polymorphism Influences the Prevalence of Diabetes Mellitus and Pro-Atherogenic Dyslipidemia in Patients with Psoriasis. J Clin Med 2022; 11:jcm11216235. [PMID: 36362461 PMCID: PMC9656109 DOI: 10.3390/jcm11216235] [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: 09/04/2022] [Revised: 10/19/2022] [Accepted: 10/20/2022] [Indexed: 11/07/2022] Open
Abstract
Background: The co-inhibitory molecule B7-H4 is located in the genomic regions associated with type 1 diabetes (T1D) susceptibility. However, the correlation of B7-H4 with glycometabolism and dyslipidemia has never been studied. Objective: To explore the influence of B7-H4 polymorphism on the prevalence of diabetes mellitus (DM) and dyslipidemia in psoriasis. Methods: In this single-center cross-sectional study, we recruited 265 psoriatic patients receiving methotrexate (MTX) treatment. Thirteen single-nucleotide polymorphisms (SNPs) in B7-H4 were genotyped. Serum levels of total cholesterol (TC), triglycerides (TG), lipoprotein (a) (LP(a)), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein (LDL), apolipoprotein A1 (ApoA1), and apolipoprotein B (ApoB) were measured at baseline and week 12. Results: The GG genotype carriers of rs12025144 in B7-H4 had a higher prevalence of DM (57.14% vs. 17.71% vs. 18.67%, p = 0.0018), and had a poorer response to MTX in diabetic patients (p < 0.05), compared with AA or AG genotype carriers. The AG genotype of rs2066398 was associated with higher levels of pro-atherogenic lipids. MTX significantly downregulated the level of anti-atherogenic lipid ApoA1 in AA genotype carriers of rs2066398. Conclusions: The genotypes rs12025144 and rs2066398 in B7-H4 were correlated with a higher prevalence of DM and dyslipidemia in psoriasis, respectively.
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Affiliation(s)
- Wenjing Yang
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Qiong Huang
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Ling Han
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Bing Wang
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Nikhil Yawalkar
- Department of Dermatology, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland
| | - Zhenghua Zhang
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai 200040, China
- Correspondence: (Z.Z.); (K.Y.)
| | - Kexiang Yan
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai 200040, China
- Correspondence: (Z.Z.); (K.Y.)
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11
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Ren X, Li Y, Nishimura C, Zang X. Crosstalk between the B7/CD28 and EGFR pathways: Mechanisms and therapeutic opportunities. Genes Dis 2022; 9:1181-1193. [PMID: 35873032 PMCID: PMC9293717 DOI: 10.1016/j.gendis.2021.08.009] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2021] [Revised: 08/20/2021] [Accepted: 08/24/2021] [Indexed: 12/31/2022] Open
Abstract
Somatic activating mutations in the epidermal growth factor receptor (EGFR) are one of the most common oncogenic drivers in cancers such as non-small-cell lung cancer (NSCLC), metastatic colorectal cancer, glioblastoma, head and neck cancer, pancreatic cancer, and breast cancer. Molecular-targeted agents against EGFR signaling pathways have shown robust clinical efficacy, but patients inevitably experience acquired resistance. Although immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 have exhibited durable anti-tumor responses in a subset of patients across multiple cancer types, their efficacy is limited in cancers harboring activating gene alterations of EGFR. Increasing studies have demonstrated that upregulation of new B7/CD28 family members such as B7-H3, B7x and HHLA2, is associated with EGFR signaling and may contribute to resistance to EGFR-targeted therapies by creating an immunosuppressive tumor microenvironment (TME). In this review, we discuss the regulatory effect of EGFR signaling on the PD-1/PD-L1 pathway and new B7/CD28 family member pathways. Understanding these interactions may inform combination therapeutic strategies and potentially overcome the current challenge of resistance to EGFR-targeted therapies. We also summarize clinical data of anti-PD-1/PD-L1 therapies in EGFR-mutated cancers, as well as ongoing clinical trials of combination of EGFR-targeted therapies and anti-PD-1/PD-L1 immunotherapies.
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Affiliation(s)
- Xiaoxin Ren
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, New York, NY 10461, USA
| | - Yixian Li
- Division of Pediatric Hematology/Oncology/Transplant and Cellular Therapy, Children's Hospital at Montefiore, Bronx, NY 10467, USA
| | - Christopher Nishimura
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, New York, NY 10461, USA
| | - Xingxing Zang
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, New York, NY 10461, USA.,Department of Medicine, Albert Einstein College of Medicine, New York, NY 10461, USA.,Department of Urology, Albert Einstein College of Medicine, New York, NY 10461, USA
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12
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Hassanian H, Asadzadeh Z, Baghbanzadeh A, Derakhshani A, Dufour A, Rostami Khosroshahi N, Najafi S, Brunetti O, Silvestris N, Baradaran B. The expression pattern of Immune checkpoints after chemo/radiotherapy in the tumor microenvironment. Front Immunol 2022; 13:938063. [PMID: 35967381 PMCID: PMC9367471 DOI: 10.3389/fimmu.2022.938063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Accepted: 07/07/2022] [Indexed: 11/13/2022] Open
Abstract
As a disease with the highest disease-associated burden worldwide, cancer has been the main subject of a considerable proportion of medical research in recent years, intending to find more effective therapeutic approaches with fewer side effects. Combining conventional methods with newer biologically based treatments such as immunotherapy can be a promising approach to treating different tumors. The concept of "cancer immunoediting" that occurs in the field of the tumor microenvironment (TME) is the aspect of cancer therapy that has not been at the center of attention. One group of the role players of the so-called immunoediting process are the immune checkpoint molecules that exert either co-stimulatory or co-inhibitory effects in the anti-tumor immunity of the host. It involves alterations in a wide variety of immunologic pathways. Recent studies have proven that conventional cancer therapies, such as chemotherapy, radiotherapy, or a combination of them, i.e., chemoradiotherapy, alter the "immune compartment" of the TME. The mentioned changes encompass a wide range of variations, including the changes in the density and immunologic type of the tumor-infiltrating lymphocytes (TILs) and the alterations in the expression patterns of the different immune checkpoints. These rearrangements can have either anti-tumor immunity empowering or immune attenuating sequels. Thus, recognizing the consequences of various chemo(radio)therapeutic regimens in the TME seems to be of great significance in the evolution of therapeutic approaches. Therefore, the present review intends to summarize how chemo(radio)therapy affects the TME and specifically some of the most important, well-known immune checkpoints' expressions according to the recent studies in this field.
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Affiliation(s)
- Hamidreza Hassanian
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Zahra Asadzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Baghbanzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Afshin Derakhshani
- Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, AB, Canada
- McCaig Insitute, Hotchkiss Brain Institute, and Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada
| | - Antoine Dufour
- McCaig Insitute, Hotchkiss Brain Institute, and Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada
- Departments of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada
| | | | - Souzan Najafi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Oronzo Brunetti
- Medical Oncology Unit, IRCCS Istituto Tumori Giovanni Paolo II, Bari, Italy
| | - Nicola Silvestris
- Medical Oncology Unit, Department of Human Pathology “G. Barresi” University of Messina, Messina, Italy
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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Vaishnav J, Jadeja SD, Singh M, Khan F, Yadav M, Begum R. Altered Levels of Negative Costimulatory Molecule V-Set Domain-Containing T-Cell Activation Inhibitor-1 (VTCN1) and Metalloprotease Nardilysin (NRD1) are Associated with Generalized Active Vitiligo. Immunol Invest 2022; 51:2035-2052. [PMID: 35815687 DOI: 10.1080/08820139.2022.2097091] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
BACKGROUND Vitiligo is characterized by depigmented macules on the skin caused due to autoimmune destruction of melanocytes. V-set domain-containing T-cell activation inhibitor-1 (VTCN1) is a negative costimulatory molecule that plays a vital role in suppressing autoimmunity and tuning immune response. Nardilysin (NRD1), a metalloproteinase, cleaves membrane-tethered VTCN1 resulting in the shedding of soluble-VTCN1 (sVTCN1). However, the role of VTCN1 and NRD1 in vitiligo pathogenesis is unexplored. OBJECTIVES AND METHODS This study was aimed to (i) Investigate the association of VTCN1 intronic polymorphisms (rs10923223 T/C and rs12046117 C/T) with vitiligo susceptibility in Gujarat population by using Polymerase Chain Reaction- Restriction Fragment Length Polymorphism (PCR-RFLP) (ii) Estimate VTCN1 & NRD1 transcript levels from peripheral blood mononuclear cells (PBMCs) and skin samples of vitiligo patients by real-time PCR, (iii) Estimate sVTCN1 and NRD1 protein levels from plasma by ELISA and (iv) Estimate VTCN1 protein levels in the skin samples of vitiligo patients by immunofluorescence. RESULTS The analysis revealed increased VTCN1 and NRD1 transcript levels in the skin (p = .039, p = .021 respectively), increased sVTCN1 and NRD1 levels (p = .026, p = .015 respectively) in the plasma, and decreased VTCN1 protein levels (p = .0002) in the skin of vitiligo patients as compared to healthy controls. The genetic analysis revealed no significant association of VTCN1 intronic polymorphisms rs10923223 T/C and rs12046117 C/T with vitiligo susceptibility in Gujarat population (p = .359, p = .937, respectively). CONCLUSIONS The present study revealed altered VTCN1 and NRD1 expressions in the blood and skin of vitiligo patients, suggesting their potential role in the development and progression of Vitiligo.
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Affiliation(s)
- Jayvadan Vaishnav
- Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, India
| | - Shahnawaz D Jadeja
- Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, India
| | - Mala Singh
- Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, India
| | - Farheen Khan
- Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, India
| | - Madhu Yadav
- Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, India
| | - Rasheedunnisa Begum
- Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, India
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Targeted Therapy of B7 Family Checkpoints as an Innovative Approach to Overcome Cancer Therapy Resistance: A Review from Chemotherapy to Immunotherapy. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27113545. [PMID: 35684481 PMCID: PMC9182385 DOI: 10.3390/molecules27113545] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Revised: 05/24/2022] [Accepted: 05/25/2022] [Indexed: 11/17/2022]
Abstract
It is estimated that there were 18.1 million cancer cases worldwide in 2018, with about 9 million deaths. Proper diagnosis of cancer is essential for its effective treatment because each type of cancer requires a specific treatment procedure. Cancer therapy includes one or more approaches such as surgery, radiotherapy, chemotherapy, and immunotherapy. In recent years, immunotherapy has received much attention and immune checkpoint molecules have been used to treat several cancers. These molecules are involved in regulating the activity of T lymphocytes. Accumulated evidence shows that targeting immune checkpoint regulators like PD-1/PD-L1 and CTLA-4 are significantly useful in treating cancers. According to studies, these molecules also have pivotal roles in the chemoresistance of cancer cells. Considering these findings, the combination of immunotherapy and chemotherapy can help to treat cancer with a more efficient approach. Among immune checkpoint molecules, the B7 family checkpoints have been studied in various cancer types such as breast cancer, myeloma, and lymphoma. In these cancers, they cause the cells to become resistant to the chemotherapeutic agents. Discovering the exact signaling pathways and selective targeting of these checkpoint molecules may provide a promising avenue to overcome cancer development and therapy resistance. Highlights: (1) The development of resistance to cancer chemotherapy or immunotherapy is the main obstacle to improving the outcome of these anti-cancer therapies. (2) Recent investigations have described the involvement of immune checkpoint molecules in the development of cancer therapy resistance. (3) In the present study, the molecular participation of the B7 immune checkpoint family in anticancer therapies has been highlighted. (4) Targeting these immune checkpoint molecules may be considered an efficient approach to overcoming this obstacle.
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15
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Sun X, Xie H, Zhang H, Li Z, Qi H, Yang C, Liu X, Ren L, Jiang Y, Hu X. B7-H4 reduction induced by Toxoplasma gondii infection results in dysfunction of decidual dendritic cells by regulating the JAK2/STAT3 pathway. Parasit Vectors 2022; 15:157. [PMID: 35505420 PMCID: PMC9066748 DOI: 10.1186/s13071-022-05263-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Accepted: 03/29/2022] [Indexed: 12/17/2022] Open
Abstract
Background Primary infection of Toxoplasma gondii can cause serious abnormal pregnancy outcomes such as miscarriage and stillbirth. Inhibitory molecule B7-H4 is abundantly expressed in dendritic cells (DCs) and plays an important role in maintaining immune tolerance. However, the role of B7-H4 in decidual DCs (dDCs) in T. gondii-induced abnormal pregnancy outcomes is not clear. Methods We established T. gondii-infected abnormal pregnancy model in wild-type (WT) and B7-H4 knockout (B7-H4−/−) pregnant mice in vivo and cultured primary human dDCs in vitro. The abnormal pregnancy outcomes were observed and the expression of B7-H4, functional molecules (CD80, CD86, and MHC-II or HLA-DR), indoleamine 2,3-dioxygenase (IDO), cytokines (IL-10 and IL-12), and signaling molecules JAK2/STAT3 in dDCs was detected by flow cytometry and Western blot. Results Our results showed that T. gondii infection significantly decreased B7-H4 expression in dDCs. In addition, B7-H4−/− infected pregnant mice showed much more severe abnormal pregnancy outcomes than their counterparts. Importantly, B7-H4−/− infection further regulated the expression of molecules (CD80, CD86, and MHC-II or HLA-DR), enzyme IDO, and cytokines (IL-10 and IL-12) in dDCs. We further discovered that B7-H4−/− infection impairs the JAK2/STAT3 pathway, contributing to dDC dysfunction. Conclusions Taken together, the results show that reduction of B7-H4 by T. gondii infection significantly modulates the decrease in cytokine IL-10 and enzyme IDO and the increase in cytokine IL-12, contributing to dDC dysfunction. Moreover, the JAK2/STAT3 pathway is involved in the regulation of B7-H4 by T. gondii infection and in the subsequent IDO and cytokine production, which ultimately contributes to abnormal pregnancy outcomes. Graphical Abstract ![]()
Supplementary Information The online version contains supplementary material available at 10.1186/s13071-022-05263-1.
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Affiliation(s)
- Xinyue Sun
- Department of Immunology, Binzhou Medical University, Yantai, 264003, Shandong, People's Republic of China
| | - Hongbing Xie
- Department of Immunology, Binzhou Medical University, Yantai, 264003, Shandong, People's Republic of China
| | - Haixia Zhang
- Department of Immunology, Binzhou Medical University, Yantai, 264003, Shandong, People's Republic of China
| | - Zhidan Li
- Department of Immunology, Binzhou Medical University, Yantai, 264003, Shandong, People's Republic of China
| | - Houbao Qi
- Department of Immunology, Binzhou Medical University, Yantai, 264003, Shandong, People's Republic of China
| | - Chunyan Yang
- Department of Oral Biology, Binzhou Medical University, Yantai, 264003, Shandong, People's Republic of China
| | - Xianbing Liu
- Department of Immunology, Binzhou Medical University, Yantai, 264003, Shandong, People's Republic of China
| | - Liqin Ren
- Department of Medical Genetics and Cell Biology, Binzhou Medical University, Yantai, 264003, Shandong, People's Republic of China
| | - Yuzhu Jiang
- Department of Immunology, Binzhou Medical University, Yantai, 264003, Shandong, People's Republic of China
| | - Xuemei Hu
- Department of Immunology, Binzhou Medical University, Yantai, 264003, Shandong, People's Republic of China.
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Bączkowska M, Dutsch-Wicherek MM, Przytuła E, Faryna J, Wojtyła C, Ali M, Knafel A, Ciebiera M. Expression of the Costimulatory Molecule B7-H4 in the Decidua and Placental Tissues in Patients with Placental Abruption. Biomedicines 2022; 10:biomedicines10040918. [PMID: 35453668 PMCID: PMC9033103 DOI: 10.3390/biomedicines10040918] [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: 03/17/2022] [Revised: 04/13/2022] [Accepted: 04/14/2022] [Indexed: 12/10/2022] Open
Abstract
B7 homolog 4 protein (B7-H4), a member of the B7 family, is a immunomodulatory membrane protein. The aim of the study was to evaluate the expression of this protein in the decidua and placental tissues in case of placental abruption (PA) compared to cases of retained placental tissue (RPT) and controls. Tissue samples were obtained from 47 patients with PA, 60 patients with RPT, and 41 healthy controls. The samples were stained for B7-H4 expression, analyzed by an expert pathologist, and a semi-quantitative scale was applied. A statistical analysis revealed that the expression of B7-H4 was significantly higher in the decidua in PA samples compared to samples from patients with RPT (p-value < 0.001) and healthy controls (p-value < 0.001). The expression of B7-H4 in the placental chorionic villus was significantly higher in PA samples in relation to samples from healthy controls (p-value < 0.001) but not in relation to RPT samples (p-value = 0.0853). This finding suggests that B7-H4 might play an important role in mechanisms restoring reproductive tract homeostasis. Further research is necessary in regard to the role of B7-H4 in PA.
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Affiliation(s)
- Monika Bączkowska
- Centre of Postgraduate Medical Education, Second Department of Obstetrics and Gynecology, 01-809 Warsaw, Poland; (M.B.); (A.K.)
| | | | - Ewa Przytuła
- Department of Pathology, Bielański Hospital, 01-809 Warsaw, Poland; (E.P.); (J.F.)
| | - Jan Faryna
- Department of Pathology, Bielański Hospital, 01-809 Warsaw, Poland; (E.P.); (J.F.)
| | - Cezary Wojtyła
- International Prevention Research Institute-Collaborating Centre, Calisia University, 62-800 Kalisz, Poland;
| | - Mohamed Ali
- Clinical Pharmacy Department, Faculty of Pharmacy, Ain Shams University, Cairo 11566, Egypt;
| | - Anna Knafel
- Centre of Postgraduate Medical Education, Second Department of Obstetrics and Gynecology, 01-809 Warsaw, Poland; (M.B.); (A.K.)
| | - Michał Ciebiera
- Centre of Postgraduate Medical Education, Second Department of Obstetrics and Gynecology, 01-809 Warsaw, Poland; (M.B.); (A.K.)
- Correspondence: ; Tel.: +48-607-155-177
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Microbiota-dependent activation of the myeloid calcineurin-NFAT pathway inhibits B7H3- and B7H4-dependent anti-tumor immunity in colorectal cancer. Immunity 2022; 55:701-717.e7. [PMID: 35364006 DOI: 10.1016/j.immuni.2022.03.008] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 03/10/2022] [Accepted: 03/11/2022] [Indexed: 02/07/2023]
Abstract
Bacterial sensing by intestinal tumor cells contributes to tumor growth through cell-intrinsic activation of the calcineurin-NFAT axis, but the role of this pathway in other intestinal cells remains unclear. Here, we found that myeloid-specific deletion of calcineurin in mice activated protective CD8+ T cell responses and inhibited colorectal cancer (CRC) growth. Microbial sensing by myeloid cells promoted calcineurin- and NFAT-dependent interleukin 6 (IL-6) release, expression of the co-inhibitory molecules B7H3 and B7H4 by tumor cells, and inhibition of CD8+ T cell-dependent anti-tumor immunity. Accordingly, targeting members of this pathway activated protective CD8+ T cell responses and inhibited primary and metastatic CRC growth. B7H3 and B7H4 were expressed by the majority of human primary CRCs and metastases, which was associated with low numbers of tumor-infiltrating CD8+ T cells and poor survival. Therefore, a microbiota-, calcineurin-, and B7H3/B7H4-dependent pathway controls anti-tumor immunity, revealing additional targets for immune checkpoint inhibition in microsatellite-stable CRC.
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Mach P, Köninger A, Reisch B, Kimmig R, Gellhaus A. Soluble PD-L1 and B7-H4 serum levels during the course of physiological pregnancy. Am J Reprod Immunol 2022; 87:e13519. [PMID: 34974633 DOI: 10.1111/aji.13519] [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: 09/07/2021] [Revised: 11/04/2021] [Accepted: 12/28/2021] [Indexed: 11/30/2022] Open
Abstract
PROBLEM The aim of this study was to evaluate the soluble programmed death-ligand (sPD-L1) and soluble B7-H4 (sB7-H4) serum concentration levels longitudinal throughout the three trimesters of uncomplicated pregnancies. METHOD OF THE STUDY: sPD-L1 and sB7-H4 levels were determined with enzyme-linked immunosorbent assay (ELISA). The patients (n = 26) were divided into three groups according to the pregnancy trimester. Among 26 women involved in the study 14 had longitudinal sB7-H4 and sPD-L1 measurements in each trimester of pregnancy. RESULTS During the course of pregnancy, the sB7-H4 blood serum levels were significant higher in second trimester than in first and third trimester, whereas sPD-L1 levels increased significantly over the course of pregnancy. CONCLUSION The highest serum levels of sPD-L1 in the third trimester suggest increasing suppression of maternal immunity throughout pregnancy, whereas elevated sB7-H4 concentration levels in second trimester suggests different profile of T-cell regulation in physiological pregnancy.
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Affiliation(s)
- Pawel Mach
- Department of Obstetrics and Gynecology, University Hospital of Essen, Essen, Germany
| | - Angela Köninger
- Department of Obstetrics and Gynecology, University of Regensburg, Hospital of the Barmherzige Brueder, Clinic St Hedwig, Regensburg, Germany
| | - Beatrix Reisch
- Department of Obstetrics and Gynecology, University Hospital of Essen, Essen, Germany
| | - Rainer Kimmig
- Department of Obstetrics and Gynecology, University Hospital of Essen, Essen, Germany
| | - Alexandra Gellhaus
- Department of Obstetrics and Gynecology, University Hospital of Essen, Essen, Germany
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19
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Expression of Immune Checkpoints in Malignant Tumors: Therapy Targets and Biomarkers for the Gastric Cancer Prognosis. Diagnostics (Basel) 2021; 11:diagnostics11122370. [PMID: 34943606 PMCID: PMC8700640 DOI: 10.3390/diagnostics11122370] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 12/13/2021] [Accepted: 12/14/2021] [Indexed: 02/07/2023] Open
Abstract
To increase the effectiveness of anticancer therapy based on immune checkpoint (IC) inhibition, some ICs are being investigated in addition to those used in clinic. We reviewed data on the relationship between PD-L1, B7-H3, B7-H4, IDO1, Galectin-3 and -9, CEACAM1, CD155, Siglec-15 and ADAM17 expression with cancer development in complex with the results of clinical trials on their inhibition. Increased expression of the most studied ICs—PD-L1, B7-H3, and B7-H4—is associated with poor survival; their inhibition is clinically significant. Expression of IDO1, CD155, and ADAM17 is also associated with poor survival, including gastric cancer (GC). The available data indicate that CD155 and ADAM17 are promising targets for immune therapy. However, the clinical trials of anti-IDO1 antibodies have been unsatisfactory. Expression of Galectin-3 and -9, CEACAM1 and Siglec-15 demonstrates a contradictory relationship with patient survival. The lack of satisfactory results of these IC inhibitor clinical trials additionally indicates the complex nature of their functioning. In conclusion, in many cases it is important to analyze the expression of other participants of the immune response besides target IC. The PD-L1, B7-H3, B7-H4, IDO1 and ADAM17 may be considered as candidates for prognosis markers for GC patient survival.
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20
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Bolandi N, Derakhshani A, Hemmat N, Baghbanzadeh A, Asadzadeh Z, Afrashteh Nour M, Brunetti O, Bernardini R, Silvestris N, Baradaran B. The Positive and Negative Immunoregulatory Role of B7 Family: Promising Novel Targets in Gastric Cancer Treatment. Int J Mol Sci 2021; 22:ijms221910719. [PMID: 34639059 PMCID: PMC8509619 DOI: 10.3390/ijms221910719] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 09/28/2021] [Accepted: 10/01/2021] [Indexed: 12/30/2022] Open
Abstract
Gastric cancer (GC), with a heterogeneous nature, is the third leading cause of death worldwide. Over the past few decades, stable reductions in the incidence of GC have been observed. However, due to the poor response to common treatments and late diagnosis, this cancer is still considered one of the lethal cancers. Emerging methods such as immunotherapy with immune checkpoint inhibitors (ICIs) have transformed the landscape of treatment for GC patients. There are presently eleven known members of the B7 family as immune checkpoint molecules: B7-1 (CD80), B7-2 (CD86), B7-H1 (PD-L1, CD274), B7-DC (PDCD1LG2, PD-L2, CD273), B7-H2 (B7RP1, ICOS-L, CD275), B7-H3 (CD276), B7-H4 (B7x, B7S1, Vtcn1), B7-H5 (VISTA, Gi24, DD1α, Dies1 SISP1), B7-H6 (NCR3LG1), B7-H7 (HHLA2), and Ig-like domain-containing receptor 2 (ILDR2). Interaction of the B7 family of immune-regulatory ligands with the corresponding receptors resulted in the induction and inhibition of T cell responses by sending co-stimulatory and co-inhibitory signals, respectively. Manipulation of the signals provided by the B7 family has significant potential in the management of GC.
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Affiliation(s)
- Nadia Bolandi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 516615731, Iran; (N.B.); (A.D.); (N.H.); (A.B.); (Z.A.); (M.A.N.)
- Department of Biochemistry, Faculty of Medicine, Urmia University of Medical Sciences, Urmia 571478334, Iran
| | - Afshin Derakhshani
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 516615731, Iran; (N.B.); (A.D.); (N.H.); (A.B.); (Z.A.); (M.A.N.)
- Laboratory of Experimental Pharmacology, IRCCS Istituto Tumori Giovanni Paolo II, 70124 Bari, Italy
| | - Nima Hemmat
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 516615731, Iran; (N.B.); (A.D.); (N.H.); (A.B.); (Z.A.); (M.A.N.)
| | - Amir Baghbanzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 516615731, Iran; (N.B.); (A.D.); (N.H.); (A.B.); (Z.A.); (M.A.N.)
| | - Zahra Asadzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 516615731, Iran; (N.B.); (A.D.); (N.H.); (A.B.); (Z.A.); (M.A.N.)
| | - Mina Afrashteh Nour
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 516615731, Iran; (N.B.); (A.D.); (N.H.); (A.B.); (Z.A.); (M.A.N.)
- Department of Biochemistry, Faculty of Medicine, Urmia University of Medical Sciences, Urmia 571478334, Iran
| | - Oronzo Brunetti
- Medical Oncology Unit—IRCCS Istituto Tumori “Giovanni Paolo II” of Bari, 70124 Bari, Italy;
| | - Renato Bernardini
- Department of Biomedical and Biotechnological Sciences, University of Catania, Via S. Sofia 97, 95100 Catania, Italy;
| | - Nicola Silvestris
- Medical Oncology Unit—IRCCS Istituto Tumori “Giovanni Paolo II” of Bari, 70124 Bari, Italy;
- Department of Biomedical Sciences and Human Oncology (DIMO), University of Bari, 70124 Bari, Italy
- Correspondence: (N.S.); (B.B.); Tel.: +98-413-3371440 (B.B.); Fax: +98-413-3371311 (B.B.)
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 516615731, Iran; (N.B.); (A.D.); (N.H.); (A.B.); (Z.A.); (M.A.N.)
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz 516615731, Iran
- Pharmaceutical Analysis Research Center, Tabriz University of Medical Sciences, Tabriz 516615731, Iran
- Correspondence: (N.S.); (B.B.); Tel.: +98-413-3371440 (B.B.); Fax: +98-413-3371311 (B.B.)
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21
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Ahmad A. Epigenetic regulation of immunosuppressive tumor-associated macrophages through dysregulated microRNAs. Semin Cell Dev Biol 2021; 124:26-33. [PMID: 34556420 DOI: 10.1016/j.semcdb.2021.09.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Revised: 08/02/2021] [Accepted: 09/02/2021] [Indexed: 02/06/2023]
Abstract
Macrophages are immune cells that play different roles under different physiological conditions. They are present in all tissues where they primarily protect from bacteria and pathogens in addition to assisting in tissue repair. During tumor progression, macrophages can exert contrasting effects based on the M1 vs. M2 polarization. The M2 macrophages support tumor growth through mechanisms that help suppress immune responses and/or circumvent immune-surveillance. A number of such mechanisms such as production of IL-10 and arginase, and expression of PD-L1, V-domain Ig suppressor of T cell activation and B7 family molecule B7-H4 are now believed central to the immunosuppressive effects of tumor-associated macrophages (TAMs). Emerging data has identified epigenetic regulation of these immunosuppressive mechanisms by small non-coding RNAs, the microRNAs (miRNAs). This review discusses the available literature on the subject, including the exosomes mediated transfer of miRNAs between cancer cells and the macrophages within the tumor microenvironment. A number of miRNAs are now believed to be involved in TAMs' production of IL-10 and expression of PD-L1 while the information on such regulation of other immunosuppressive mechanisms is slowly emerging. A better understanding of epigenetic regulation of macrophages-mediated immunosuppressive effect can help identify novel targets for therapy and aid the design of future studies aimed at sensitizing tumors to immune responses.
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Affiliation(s)
- Aamir Ahmad
- Interim Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar.
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22
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Miao G, Sun X. Development of a novel anti-B7-H4 antibody enhances anti-tumor immune response of human T cells. Biomed Pharmacother 2021; 141:111913. [PMID: 34328096 DOI: 10.1016/j.biopha.2021.111913] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 06/24/2021] [Accepted: 07/06/2021] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND B7-H4 is a member of the B7 superfamily that is expressed on the surface of tumors and exhibits limited expression on normal tissue. B7-H4 negatively regulates tumor immunity by interacting with the B7-H4 receptor, which is expressed by activated CD8 + T cells. Hence, we sought to generate an immunomodulatory antibody that targets B7-H4 and blocks the immunosuppressive activity of B7-H4. METHODS Anti-B7-H4 antibodies were generated using the hybridoma technique and screened by a binding assay based on B7-H4-expressing tumor cells. The B7-H4 antagonistic antibodies were further screened based on their checkpoint blockade activity using a SEB-stimulated peripheral blood mononuclear cell (PBMC) assay, which comprised B7-H4-expressing antigen presenting cells (APCs) and activated T cells. To assess the immunomodulatory activity of anti-B7-H4 antibodies, activated human CD8+ T cells were cultured in B7-H4 protein-coated plates, and the production of IL-2 and the proliferation rate of CD8+ T cells were measured. In addition, we evaluated the ADCC effect of anti-B7-H4 antibodies against tumor cell lines. The in vivo antitumor efficacy of the anti-B7-H4 antibody was also evaluated in human T cell-engrafted NOG mice. RESULTS A panel of anti-B7-H4 antibodies was generated. The top 23 antibodies were screened to identify antibodies that disabled B7-H4-mediated inhibition. Antibody 17 exhibited the greatest induction of the production of IL-2 and IFN-gamma in SEB-stimulated PBMCs. Antibody 17 was constructed as a chimeric antibody (CH17) with a human IgG1 constant domain. CH17 showed high affinity for human B7-H4 and fully cross-reacted with cynomolgus B7-H4. Additionally, CH17 mediated potent antibody-dependent cell cytotoxicity (ADCC) against different B7-H4-positive tumor cell lines. More importantly, CH17 relieved B7-H4-mediated T cell suppression by enhancing IL2 production and promoting T cell proliferation. In an MDA-MB-468-bearing mouse model in which human pan-T cells were engrafted, CH17 delayed tumor growth by engaging T cells and exerted a synergistic effect in combination with an anti-human PD-1 antibody. CONCLUSIONS We successfully generated an immunomodulatory antibody targeting B7-H4 that possesses both T cell immune checkpoint inhibitory activity and ADCC activity in B7-H4-positive tumors. B7-H4-targeting antibodies might represent a promising immunotherapy for B7-H4-expressing tumors.
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Affiliation(s)
- Guojuan Miao
- Department of pharmacy, The First People's Hospital of Xiaoshan District, Hangzhou 311200, China
| | - Xiuhong Sun
- Department of pharmacy, The First People's Hospital of Xiaoshan District, Hangzhou 311200, China.
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23
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Cai D, Wang F, Wang C, Jin L. Phenotypic and Functional Analyses of B7S1 in Ovarian Cancer. Front Mol Biosci 2021; 8:686803. [PMID: 34307455 PMCID: PMC8299558 DOI: 10.3389/fmolb.2021.686803] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2021] [Accepted: 06/28/2021] [Indexed: 12/24/2022] Open
Abstract
Background: Although programmed death (PD) ligand 1 (PD-L1)/PD-1 inhibitors show potent and durable antitumor effects in a variety of tumors, their efficacy in patients with OvCa is modest. Thus, additional immunosuppressive mechanisms beyond PD-L1/PD-1 need to be identified. Methods: The mRNA expression profiles of OvCa patients were obtained from The Cancer Genome Atlas (TCGA) database. The expression and clinical characteristics of VTCN1 (encoding B7S1) in OvCa were analyzed. The molecular interaction network, Gene Ontology (GO) analysis and Gene set enrichment analysis (GSEA) were used to functionally annotate and predict signaling pathways of VTCN1 in OvCa. Moreover, 32 treatment-naïve patients with OvCa were recruited to assess B7S1 expression. The cytotoxic immune phenotypes in distinct subgroups were analyzed. Results: B7S1 expression was increased in tumor sections compared with that in normal tissues from OvCa patients at both the mRNA and protein levels. VTCN1 expression was significantly correlated with the mRNA expression levels of several other co-inhibitory immune checkpoints. B7S1 protein was found to be highly expressed in CD45+CD68+ myeloid cells, whereas its putative receptor was expressed in CD8+ tumor-infiltrating lymphocytes (TILs). Furthermore, expression of B7S1 in antigen-presenting cells (APCs) was significantly correlated with the cytolytic function of CD8+ TILs. Functional annotations indicated that VTCN1 was involved in regulating T cell-mediated immune responses and participated in the activation of a variety of classic signaling pathways related to the progression of human cancer. Conclusion: In OvCa, B7S1 was highly expressed and may initiate dysfunction of CD8+ TILs, which could be targeted for cancer immunotherapy.
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Affiliation(s)
- Dongli Cai
- Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, School of Medicine,Tongji University, Shanghai, China
| | - Fang Wang
- Department of Gynaecology, Shanghai East Hospital, School of Medicine,Tongji University, Shanghai, China
| | - Changgang Wang
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Liping Jin
- Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, School of Medicine,Tongji University, Shanghai, China
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24
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Cao W, Ma X, Fischer JV, Sun C, Kong B, Zhang Q. Immunotherapy in endometrial cancer: rationale, practice and perspectives. Biomark Res 2021; 9:49. [PMID: 34134781 PMCID: PMC8207707 DOI: 10.1186/s40364-021-00301-z] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 05/25/2021] [Indexed: 12/12/2022] Open
Abstract
Tumor immunotherapy has attracted more and more attention nowadays, and multiple clinical trials have confirmed its effect in a variety of solid tumors. Immune checkpoint inhibitors (ICIs), cancer vaccines, adoptive cell transfer (ACT), and lymphocyte-promoting cytokines are the main immunotherapy methods. Endometrial cancer (EC) is one of the most frequent tumors in women and the prognosis of recurrent or metastatic EC is poor. Since molecular classification has been applied to EC, immunotherapy for different EC subtypes (especially POLE and MSI-H) has gradually attracted attention. In this review, we focus on the expression and molecular basis of the main biomarkers in the immunotherapy of EC firstly, as well as their clinical application significance and limitations. Blocking tumor immune checkpoints is one of the most effective strategies for cancer treatment in recent years, and has now become the focus in the field of tumor research and treatment. We summarized clinical date of planned and ongoing clinical trials and introduced other common immunotherapy methods in EC, such as cancer vaccine and ACT. Hormone aberrations, metabolic syndrome (MetS) and p53 mutant and that affect the immunotherapy of endometrial cancer will also be discussed in this review.
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Affiliation(s)
- Wenyu Cao
- Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, 107 West Wenhua Road, Ji'nan, Shandong, 250012, P.R. China.,Gynecology Oncology Key Laboratory, Qilu Hospital, Shandong University, Ji'nan, Shandong, 250012, P.R. China
| | - Xinyue Ma
- Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, 107 West Wenhua Road, Ji'nan, Shandong, 250012, P.R. China.,Gynecology Oncology Key Laboratory, Qilu Hospital, Shandong University, Ji'nan, Shandong, 250012, P.R. China
| | - Jean Victoria Fischer
- Department of Pathology, Northwestern Medicine, Gynecologic Pathology Fellow, Chicago, Illinois, USA
| | - Chenggong Sun
- Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, 107 West Wenhua Road, Ji'nan, Shandong, 250012, P.R. China.,Gynecology Oncology Key Laboratory, Qilu Hospital, Shandong University, Ji'nan, Shandong, 250012, P.R. China
| | - Beihua Kong
- Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, 107 West Wenhua Road, Ji'nan, Shandong, 250012, P.R. China.,Gynecology Oncology Key Laboratory, Qilu Hospital, Shandong University, Ji'nan, Shandong, 250012, P.R. China
| | - Qing Zhang
- Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, 107 West Wenhua Road, Ji'nan, Shandong, 250012, P.R. China. .,Gynecology Oncology Key Laboratory, Qilu Hospital, Shandong University, Ji'nan, Shandong, 250012, P.R. China.
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25
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Ding S, Zhou H, Gu Y, Shen Y, Zhang L, Zhao H, Wu J, Zhang X, Chang X, Liu C. Establishment of a novel double-monoclonal antibody sandwich enzyme-linked immunosorbent assay (ELISA): tool for human B7-H4 detection in autoimmune diseases. Clin Exp Immunol 2021; 205:150-159. [PMID: 33961296 DOI: 10.1111/cei.13610] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 04/19/2021] [Accepted: 04/19/2021] [Indexed: 12/25/2022] Open
Abstract
B7-H4, one of the immunoregulatory proteins, plays an inhibitory role by inhibiting T cell proliferation and cytokine production. Nevertheless, the significance of soluble B7-H4 (sB7-H4) in autoimmune diseases is unclear. In our study, we developed two novel mouse anti-human B7-H4 monoclonal antibodies (mAbs) (clones 8D4 and 7E1) with utilities for flow cytometry, immunoblotting and immunofluorescence. We characterized 7E1 as a functional antibody with antagonistic activity, which could promote T cell proliferation and regulate cytokine production. Furthermore, based on the different epitope specificities, we established a novel enzyme-linked immunosorbent assay (ELISA) which could detect sB7-H4 sensitively and specifically. Using this ELISA kit, sB7-H4 was observed in a high proportion of autoimmune diseases patients. We found that the levels of sB7-H4 were significantly higher in patients with systemic lupus erythematosus (SLE), type I diabetes (T1D) and Graves' disease (GD). Together, sB7-H4 in human serum is regarded not only as a regulator of T cell activation but may also be a diagnostic marker of autoimmune diseases.
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Affiliation(s)
- Sisi Ding
- Jiangsu Institute of Clinical Immunology & Jiangsu Key Laboratory of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China.,Suzhou Key Laboratory for Tumor Immunology of Digestive Tract, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Hengxin Zhou
- Jiangsu Institute of Clinical Immunology & Jiangsu Key Laboratory of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China.,Suzhou Key Laboratory for Tumor Immunology of Digestive Tract, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Yanzheng Gu
- Jiangsu Institute of Clinical Immunology & Jiangsu Key Laboratory of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China.,Suzhou Key Laboratory for Tumor Immunology of Digestive Tract, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Yu Shen
- Jiangsu Institute of Clinical Immunology & Jiangsu Key Laboratory of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China.,Suzhou Key Laboratory for Tumor Immunology of Digestive Tract, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Li Zhang
- Soochow University-Bright Scistar Antibody Joint Laboratory, Suzhou, China
| | - Huayang Zhao
- Soochow University-Bright Scistar Antibody Joint Laboratory, Suzhou, China
| | - Jian Wu
- Jiangsu Institute of Clinical Immunology & Jiangsu Key Laboratory of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Xueguang Zhang
- Jiangsu Institute of Clinical Immunology & Jiangsu Key Laboratory of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Xin Chang
- Jiangsu Institute of Clinical Immunology & Jiangsu Key Laboratory of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Cuiping Liu
- Jiangsu Institute of Clinical Immunology & Jiangsu Key Laboratory of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China.,Suzhou Key Laboratory for Tumor Immunology of Digestive Tract, The First Affiliated Hospital of Soochow University, Suzhou, China
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26
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Duan L, Reisch B, Iannaccone A, Hadrovic E, Wu Y, Vogtmann R, Winterhager E, Kimmig R, Köninger A, Mach P, Gellhaus A. Abnormal expression of the costimulatory molecule B7-H4 in placental chorionic villous and decidual basalis tissues of patients with preeclampsia and HELLP syndrome. Am J Reprod Immunol 2021; 86:e13430. [PMID: 33864713 DOI: 10.1111/aji.13430] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Revised: 03/24/2021] [Accepted: 04/12/2021] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND B7-H4, a checkpoint molecule of the B7 family, regulates a broad spectrum such as T-cell activation, cytokine secretion, tumour progression, and invasion capacities. Our previous data revealed that soluble B7-H4 (sB7-H4) blood serum levels are elevated in women at high risk for the hypertensive pregnancy disorder preeclampsia (PE) in the first trimester, as well as in patients with confirmed early/late-onset PE. AIM We here aim to investigate the expression pattern of B7-H4 in placental tissues of PE and HELLP Syndrome versus control group. METHODS B7-H4 protein expression and localization were investigated by immunoblotting and co-immunohistochemistry in placental chorionic villous and decidual basalis tissues. RESULTS B7-H4 protein was prominently expressed at the cell membrane, in the cytoplasm of the syncytiotrophoblast (STB) and interstitial extravillous trophoblast (EVT). B7-H4 protein levels in placental chorionic villous tissue were significantly higher in women with early-onset/late-onset PE and HELLP, while it was decreased in decidual basalis tissues of early-onset PE and HELLP compared with controls. CONCLUSION B7-H4 was inversely expressed in placental chorionic villous and decidual basalis tissues of PE and HELLP patients. The increase in B7-H4 in the STB in PE and HELLP may lead to excessive apical expression and release of soluble B7-H4 in the maternal circulation. In contrast, the decrease in B7-H4 in decidual basalis tissues could be related to the decrease in invasion ability of the EVT in PE. Thus, the current results strongly suggest that B7-H4 is involved in the pathogenesis of PE and HELLP.
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Affiliation(s)
- Liyan Duan
- Department of Gynecology and Obstetrics, University of Duisburg-Essen, Essen, Germany
| | - Beatrix Reisch
- Department of Gynecology and Obstetrics, University of Duisburg-Essen, Essen, Germany
| | - Antonella Iannaccone
- Department of Gynecology and Obstetrics, University of Duisburg-Essen, Essen, Germany
| | - Elina Hadrovic
- Department of Gynecology and Obstetrics, University of Duisburg-Essen, Essen, Germany
| | - Yuqing Wu
- Institute of Molecular Biology, University of Duisburg-Essen, Essen, Germany
| | - Rebekka Vogtmann
- Department of Gynecology and Obstetrics, University of Duisburg-Essen, Essen, Germany
| | | | - Rainer Kimmig
- Department of Gynecology and Obstetrics, University of Duisburg-Essen, Essen, Germany
| | - Angela Köninger
- Department of Gynecology and Obstetrics, University of Duisburg-Essen, Essen, Germany.,Department of Gynecology and Obstetrics, Clinic of the Order of St. John, St. Hedwigs Clinic, Regensburg, Germany
| | - Pawel Mach
- Department of Gynecology and Obstetrics, University of Duisburg-Essen, Essen, Germany
| | - Alexandra Gellhaus
- Department of Gynecology and Obstetrics, University of Duisburg-Essen, Essen, Germany
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27
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Ding S, Lv X, Liu Z, Zhan S, Xu Y, Zhang X, Liu C, Cao L. Overexpression of B7-H4 is associated with infiltrating immune cells and poor prognosis in metastatic colorectal cancer. Int Immunopharmacol 2021; 90:107144. [PMID: 33187907 DOI: 10.1016/j.intimp.2020.107144] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Revised: 10/22/2020] [Accepted: 10/23/2020] [Indexed: 01/31/2023]
Abstract
Metastasis commonly occurs in colorectal cancer (CRC) patients and confers a poor prognosis. B7-H4, an immune checkpoint molecule, has been found to be expressed in numerous tumor tissues and play critical roles in tumor progression. However, B7-H4 expression and its prognostic significance in different metastases from CRC remain unclear. In the present study, we screened a novel mouse anti-human B7-H4 monoclonal antibody (mAb) which exhibited a higher degree of recognition and sensitivity than the commercial reagent in immunohistochemistry (IHC). Using this antibody, overall 110 metastatic and paired primary lesions of CRC were analyzed for their expression of B7-H4, CD8 and CD68. Our results showed that expression of B7-H4 and CD68 in metastastic lesions was significantly higher than that in matched primary lesions (P = 0.0016, P < 0.0001). We also found a significant increase of CD68-positive immune cell infiltration in the B7-H4 high expressing metastases (P = 0.041). Moreover, upregulated B7-H4 in metastatic lesions was correlated with poor prognosis of patients (P = 0.014), while in primary lesions, B7-H4 combined with CD8 was associated with the overall survival (OS) (P = 0.043). Further, B7-H4 expression in metastatic lesions was significantly correlated with hazard ratio (HR) both in univariate and multivariate analysis. Altogether, B7-H4 in metastatic lesions is promising to be a potential prognostic indicator of CRC, and may promote tumor progression and metastasis of this cancer.
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Affiliation(s)
- Sisi Ding
- Jiangsu Institute of Clinical Immunology & Jiangsu Key Laboratory of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Xinlu Lv
- Department of Laboratory Medicine, The First People's Hospital of Taicang, Taicang Hospital Affiliated to Soochow University, Suzhou, China
| | - Zhiju Liu
- Department of Pathology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Shenghua Zhan
- Department of Pathology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Yunyun Xu
- Institute of Pediatrics, Children's Hospital of Soochow University, Suzhou, China
| | - Xueguang Zhang
- Jiangsu Institute of Clinical Immunology & Jiangsu Key Laboratory of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Cuiping Liu
- Jiangsu Institute of Clinical Immunology & Jiangsu Key Laboratory of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China.
| | - Lei Cao
- Jiangsu Institute of Clinical Immunology & Jiangsu Key Laboratory of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China.
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Silveira DA, Ribeiro FM, Simão ÉM, Mattos VLD, Góes EG. Expression of genes and pathways associated with the B7-CD28 superfamily in response to irradiation of blood cells using 137Cs. Int J Radiat Biol 2020; 97:149-155. [PMID: 33253600 DOI: 10.1080/09553002.2021.1857454] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
PURPOSE DNA damage is one of the main consequences of exposure to ionizing irradiation (IR). Recent studies indicate that IR can modulate the expression of immune system-related genes. However, the effects of IR on the expression of genes and pathways of the B7-CD28 superfamily remain poorly defined. The aim of this study was to evaluate the modulation of genes and pathways related to the B7-CD28 superfamily in response to IR. MATERIALS AND METHODS In this study, we used transcriptome data available from the Gene Expression Omnibus (GEO) database to investigate the modulation of the response of genes and pathways of samples of human peripheral blood irradiated with doses of 150, 300, and 600 cGy. The data were obtained at 6 and 24 h after irradiation. The relationship between genes and pathways was established through the Reactome database. The behavior of these pathways was analyzed using mathematical methods based on relative activity and diversity. Analysis of variance (ANOVA) followed by multiple comparisons tests (Bonferroni and Tamhanes) was used to identify differentially expressed genes. Data on transcriptomes were analyzed through ViaComplex V.1.0 and IBM SPSS Statistics 22. RESULTS For the pathways investigated in this study, we observed that the effects produced by these doses significantly modified the behavior of five pathways associated with the immune system. Also, the dose of 300 cGy might trigger signaling for the activation of T cells through the negative regulation (p < .05) of the co-inhibitory PDCD1LG2 gene. Positive regulation caused by 300 cGy (p < .05) of the CD80 receptor was observed by us, which might be related to a stimulatory signal. According to our findings, this dose induced the production of cytokines and genes that are associated with the activation and differentiation of T cells. CONCLUSIONS Our findings indicate that the irradiation modulated the organization of the biological system, suggesting that 300 cGy is more efficient in activating the immune system.
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Affiliation(s)
- Daner A Silveira
- Institute of Mathematics, Statistics and Physics, Federal University of Rio Grande, Rio Grande, Brazil
| | - Fernanda M Ribeiro
- Institute of Mathematics, Statistics and Physics, Federal University of Rio Grande, Rio Grande, Brazil
| | - Éder M Simão
- Nanoscience Graduate Program, Franciscan University, Santa Maria, Brazil
| | - Viviane L D Mattos
- Institute of Mathematics, Statistics and Physics, Federal University of Rio Grande, Rio Grande, Brazil
| | - Evamberto G Góes
- Institute of Mathematics, Statistics and Physics, Federal University of Rio Grande, Rio Grande, Brazil
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Cheng Z, Liu Z, Yuan Y, Liu Z, He Y, Jiang P. Predictive value of serum soluble B7-H4 in acute pancreatitis. Eur J Clin Invest 2020; 50:e13346. [PMID: 32648937 DOI: 10.1111/eci.13346] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Revised: 06/06/2020] [Accepted: 06/23/2020] [Indexed: 12/16/2022]
Abstract
BACKGROUND Studies reported that soluble B7-H4 (sB7-H4) was significantly related to the progression and prognosis of inflammatory diseases, and whether sB7-H4 is related to the severity and prognosis of acute pancreatitis (AP) timely has not been reported. MATERIALS AND METHODS Clinical database data of 446 AP patients were retrospectively collected, and the correlation between the expression serum levels of sB7-H4 with inflammatory factors and prognostic scores was analysed in AP patients. RESULTS Soluble B7-H4 was significantly correlated with IL-6, IL-8, TNF-α, PCT, CRP levels and WBC count (P < .01), with correlation coefficients of R = .61, .53, .46, .60, .57 and .47, respectively, and AUCs were 0.905, 0.837, 0.797, 0.858, 0.890, 0.841 and 0.855, respectively. In addition, sB7-H4 was significantly correlated with the Ranson score, APACHE II score and BISAP score (P < .001), with correlation coefficients of R = .58, .63 and .59, respectively. The AUCs of assessing local complications of AP were 0.908, 0.863, 0.785 and 0.844, respectively; assessing organ failure were 0.872, 0.790, 0.796 and 0.857, respectively; and assessing in-hospital mortality were 0.839, 0.821, 0.796 and 0.823, respectively. CONCLUSIONS Soluble B7-H4 could be used as a marker for the diagnosis, severity assessment and poor prognosis assessment of AP patients, which may have potential clinical applications.
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Affiliation(s)
- Zhixiang Cheng
- Department Hepatobiliary & Pancreat Surgery, Zhongnan Hospital, Wuhan University, Wuhan, China
| | - Zhengfang Liu
- Department Neurology, Wuhan Fourth Hospital, Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yufeng Yuan
- Department Hepatobiliary & Pancreat Surgery, Zhongnan Hospital, Wuhan University, Wuhan, China
| | - Zhisu Liu
- Department Hepatobiliary & Pancreat Surgery, Zhongnan Hospital, Wuhan University, Wuhan, China
| | - Yueming He
- Department Hepatobiliary & Pancreat Surgery, Zhongnan Hospital, Wuhan University, Wuhan, China
| | - Ping Jiang
- Department Hepatobiliary & Pancreat Surgery, Zhongnan Hospital, Wuhan University, Wuhan, China
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B7-H4 Inhibits the Development of Primary Sjögren's Syndrome by Regulating Treg Differentiation in NOD/Ltj Mice. J Immunol Res 2020; 2020:4896727. [PMID: 33062721 PMCID: PMC7537676 DOI: 10.1155/2020/4896727] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2020] [Revised: 08/30/2020] [Accepted: 09/10/2020] [Indexed: 11/29/2022] Open
Abstract
Background This study is aimed at exploring the role of B7-H4 in the pathogenesis of primary Sjögren's syndrome (pSS) in NOD/Ltj mouse. Methods B7-H4 expression in salivary glands was examined by IHC, and lymphocyte infiltration was showed by H&E. Next, anti-B7-H4 mAb or immunoglobulin isotype was injected into NOD/Ltj mice. Cytokine levels were measured by quantitative RT-PCR, and immunoglobulins were measured by ELISA. T cell subsets were analyzed by flow cytometry. Last, we treated NOD/Ltj mice with B7-H4Ig and control Ig. CD4+Foxp3+ T cells were assessed by immunohistochemistry. Two-tailed Student's t-tests were used to detect the statistical difference in various measures between the two groups. Results B7-H4 expression was remarkably reduced in salivary glands of NOD/Ltj mice at 15 weeks compared with the NOD/Ltj mice at 8 weeks. Anti-B7-H4 mAb treatment increased lymphocyte infiltration in salivary glands. Inflammatory cytokines including IL-12, IL-18, IL-1α, TNF-α, IFN-α, and BAFF were upregulated markedly in anti-B7-H4 mAb-treated mice compared to IgG isotype-treated mice. Flow cytometry analysis showed that anti-B7-H4 mAb-treated mice had lower levels of CD4+Foxp3+/CD4+ T cells in spleen. Moreover, Foxp3 mRNA levels of salivary glands were diminished in anti-B7-H4 mAb-treated mice. Flow cytometry analysis showed that anti-B7-H4 mAb inhibited CD4+Foxp3+/CD4+ T cell production, while B7-H4Ig would promote naïve CD4+ T into Treg differentiation. Administration with B7-H4Ig displayed significantly decreased lymphocyte infiltration in salivary glands and low levels of total IgM and IgG in serum. Analysis of inflammatory cytokines in salivary glands after B7-H4Ig treatment revealed that the mRNA levels of IL-12, IL-6, IL-18, IL-1α, TNF-α, and IFN-α were significantly downregulated in B7-H4Ig-treated mice compared to control Ig treatment. B7-H4Ig-treated mice had significantly higher levels of CD4+Foxp3+/CD4+ T cells in spleen. IHC in salivary gland revealed that CD4+Foxp3+ T cells of B7-H4Ig treatment mouse were more than control Ig treatment. Conclusions Our findings implicate that B7-H4 has a protective role for salivary gland epithelial cells (SGECs) and therapeutic potential in the treatment of pSS.
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B7-H4 is Inversely Correlated With T-Cell Infiltration in Clear Cell but Not Serous or Endometrioid Ovarian Cancer. Appl Immunohistochem Mol Morphol 2020; 27:515-522. [PMID: 29189263 DOI: 10.1097/pai.0000000000000608] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
B7-H4, a tumor-associated cell surface protein, is expressed in endometrioid (EM), serous (SE), and clear cell (CC) ovarian carcinomas. Prior in vitro studies from other groups indicated that elevated B7-H4 expression by tumor cells blocks T-cell activation; therefore, it had been postulated to play a role in shielding cancer cells from immune surveillance and averting apoptotic programs. To test the validity of these hypotheses, the present study was designed to compare the immunohistochemical staining intensity of B7-H4 in tumor cells of ovarian cancers with the number of tumor-infiltrating T cells and macrophages and with the levels of caspase-3 staining in apoptotic debris. Serial tissue sections from EM, SE, and CC carcinomas were analyzed across representative cross-sections of tumor resection specimens, demonstrating different levels of B7-H4 expression, highest in CC cancers. B7-H4 staining in CC tissue sections was significantly correlated with the number of CD3, CD4, and CD8 tumor-infiltrating T cells and with the number of CD14 tumor-infiltrating macrophages, but was not significantly related to caspase-3 staining. These results support the concept that high levels of B7-H4 expression are inversely correlated with tumor T-cell infiltration and with CD14-labeled macrophages but not caspase-3 expression in CC carcinomas. We did not, however, find clear evidence of a relationship between the lower levels of B7-H4 seen in EM and SE carcinomas and T cell or macrophage infiltration. Thus, high levels of B7-H4, as seen in CC carcinomas, is associated with decreased tumor infiltration by T cells and macrophages but the lower levels of expression, as observed in EM and SE carcinomas, appear less likely to play an effective role in protection from immune surveillance. Furthermore, we found no evidence of a correlation between B7-H4 expression and apoptosis. These findings highlight the importance of further investigation of B7-H4 as an immunomodulatory protein, to support the development of novel therapeutic interventions for improved efficacy of treatments for CC carcinoma.
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Podojil JR, Glaser AP, Baker D, Courtois ET, Fantini D, Yu Y, Eaton V, Sivajothi S, Chiang M, Das A, McLaughlin KA, Robson P, Miller SD, Meeks JJ. Antibody targeting of B7-H4 enhances the immune response in urothelial carcinoma. Oncoimmunology 2020; 9:1744897. [PMID: 32363111 PMCID: PMC7185218 DOI: 10.1080/2162402x.2020.1744897] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Revised: 11/04/2019] [Accepted: 12/09/2019] [Indexed: 12/20/2022] Open
Abstract
Patients with locally advanced and metastatic urothelial carcinoma have a low survival rate (median 15.7 months, 13.1-17.8), with only a 23% response rate to monotherapy treatment with anti-PDL1 checkpoint immunotherapy. To identify new therapeutic targets, we profiled the immune regulatory signatures during murine cancer development using the BBN carcinogen and identified an increase in the expression of the T cell inhibitory protein B7-H4 (VTCN1, B7S1, B7X). B7-H4 expression temporally correlated with decreased lymphocyte infiltration. While the increase in B7-H4 expression within the bladder by CD11b+ monocytes is shared with human cancers, B7-H4 expression has not been previously identified in other murine cancer models. Higher expression of B7-H4 was associated with worse survival in muscle-invasive bladder cancer in humans, and increased B7-H4 expression was identified in luminal and luminal-papillary subtypes of bladder cancer. Evaluation of B7-H4 by single-cell RNA-Seq and immune mass cytometry of human bladder tumors found that B7-H4 is expressed in both the epithelium of urothelial carcinoma and CD68+ macrophages within the tumor. To investigate the function of B7-H4, treatment of human monocyte and T cell co-cultures with a B7-H4 blocking antibody resulted in enhanced IFN-γ secretion by CD4+ and CD8+ T cells. Additionally, anti-B7-H4 antibody treatment of BBN-carcinogen bladder cancers resulted in decreased tumor size, increased CD8+ T cell infiltration within the bladder, and a complimentary decrease in tumor-infiltrating T regulatory cells (Tregs). Furthermore, treatment with a combination of anti-PD-1 and anti-B7-H4 antibodies resulted in a significant reduction in tumor stage, a reduction in tumor size, and an increased level of tumor necrosis. These findings suggest that antibodies targeting B7-H4 may be a viable strategy for bladder cancers unresponsive to PD-1 checkpoint inhibitors.
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Affiliation(s)
- Joseph R. Podojil
- Department of Microbiology and Immunology, Feinberg School of Medicine, Chicago, IL, USA
| | - Alexander P. Glaser
- Department of Urology, Feinberg School of Medicine, Chicago, IL, USA
- Department of Biochemistry, and Molecular Genetics, Feinberg School of Medicine, Chicago, IL, USA
- Division of Urology, Department of Surgery, NorthShore University HealthSystem, Evanston, IL, USA
| | - Dylan Baker
- Single Cell Biology Laboratory, The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
- Department of Genetics and Genome Sciences, Institute for Systems Genomics, University of Connecticut, Farmington, CT, USA
| | - Elise T. Courtois
- Single Cell Biology Laboratory, The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
- Department of Genetics and Genome Sciences, Institute for Systems Genomics, University of Connecticut, Farmington, CT, USA
| | - Damiano Fantini
- Department of Urology, Feinberg School of Medicine, Chicago, IL, USA
- Department of Biochemistry, and Molecular Genetics, Feinberg School of Medicine, Chicago, IL, USA
| | - Yanni Yu
- Department of Urology, Feinberg School of Medicine, Chicago, IL, USA
- Department of Biochemistry, and Molecular Genetics, Feinberg School of Medicine, Chicago, IL, USA
| | - Valerie Eaton
- Department of Microbiology and Immunology, Feinberg School of Medicine, Chicago, IL, USA
| | - Santhosh Sivajothi
- Single Cell Biology Laboratory, The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
- Department of Genetics and Genome Sciences, Institute for Systems Genomics, University of Connecticut, Farmington, CT, USA
| | - Mingyi Chiang
- Department of Microbiology and Immunology, Feinberg School of Medicine, Chicago, IL, USA
| | - Arighno Das
- Department of Urology, Feinberg School of Medicine, Chicago, IL, USA
| | - Kimberly A. McLaughlin
- Department of Urology, Feinberg School of Medicine, Chicago, IL, USA
- Department of Biochemistry, and Molecular Genetics, Feinberg School of Medicine, Chicago, IL, USA
| | - Paul Robson
- Single Cell Biology Laboratory, The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
- Department of Genetics and Genome Sciences, Institute for Systems Genomics, University of Connecticut, Farmington, CT, USA
| | - Stephen D. Miller
- Department of Microbiology and Immunology, Feinberg School of Medicine, Chicago, IL, USA
| | - Joshua J. Meeks
- Department of Urology, Feinberg School of Medicine, Chicago, IL, USA
- Department of Biochemistry, and Molecular Genetics, Feinberg School of Medicine, Chicago, IL, USA
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Zhao Y, Zheng Q, Jin L. The Role of B7 Family Molecules in Maternal-Fetal Immunity. Front Immunol 2020; 11:458. [PMID: 32265918 PMCID: PMC7105612 DOI: 10.3389/fimmu.2020.00458] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Accepted: 02/27/2020] [Indexed: 01/08/2023] Open
Abstract
Pregnancy is a complex but well-arranged process, and a healthy fetus requires immune privilege and surveillance in the presence of paternally derived antigens. Maternal and fetal cells interact at the maternal–fetal interface. The upregulation and downregulation of maternal immunity executed by the leukocyte population predominantly depend on the activity of decidual natural killer cells and trophoblasts and are further modulated by a series of duplex signals. The B7 family, which consists of B7-1, B7-2, B7-H1, B7-DC, B7-H2, B7-H3, B7-H4, B7-H5, BTNL2, B7-H6, and B7-H7, is one of the most characterized and widely distributed signaling molecule superfamilies and conducts both stimulatory and inhibitory signals through separate interactions. In particular, the roles of B7-1, B7-2, B7-H1, and their corresponding receptors in the progression of normal pregnancy and some pregnancy complications have been extensively studied. Together with the TCR–MHC complex, B7 and its receptors play a critical role in cell proliferation and cytokine secretion. Depending on this ligand–receptor crosstalk, the balance between the tolerance and rejection of the fetus is perfectly maintained. This review aims to provide an overview of the current knowledge of the B7 family and its functions in regulating maternal–fetal immunity through individual interactions.
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Affiliation(s)
- Yongbo Zhao
- Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China
| | - Qingliang Zheng
- Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China
| | - Liping Jin
- Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China
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Li C, Zhan Y, Ma X, Fang H, Gai X. B7-H4 facilitates proliferation and metastasis of colorectal carcinoma cell through PI3K/Akt/mTOR signaling pathway. Clin Exp Med 2020; 20:79-86. [PMID: 31664539 DOI: 10.1007/s10238-019-00590-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Accepted: 10/22/2019] [Indexed: 12/16/2022]
Abstract
B7-H4 is over-expressed in various tumors and may affect many aspects of cancer biology. Our previous studies have reported that the over-expressed B7-H4 in serum or tumor tissue of colorectal carcinoma (CRC) patients was closely related to CRC progression. However, B7-H4 in cell biological characteristics of CRC is not well studied. Here, we investigate the effect of the B7-H4 on cell proliferation, migration and its expression regulated by PI3K/Akt/mTOR signaling pathway in CRC. Firstly, pSilencer 4.1-B7-H4-shRNA vector was constructed and stable transfection was performed on HT-29 cells. Secondly, cell proliferation, cell cycle, cell apoptosis and cell migration were evaluated after B7-H4 silencing, and the expression of Bcl-2, caspase-3, MMP-2 and MMP-9 was also measured. Finally, the regulation of B7-H4 by PI3K/Akt/mTOR signaling pathway was measured followed by treatment with or without PI3K/Akt and mTOR inhibitor. The results showed that the viability of HT-29 cells was significantly decreased after B7-H4 silencing (P < 0.05). B7-H4 silencing significantly increased the apoptosis rate and caspase-3 protein expression while decreased Bcl-2 protein expression (P all < 0.05). B7-H4 silencing also significantly reduced the migration of HT-29 cells (P < 0.01) and the secretion of MMP-2 or MMP-9 (P all < 0.05). Following treatment with PI3K/Akt and mTOR inhibitor in HT-29 cells, the expression of B7-H4 was significantly downregulated compared with untreated group (P all < 0.05). Our results strongly suggest that B7-H4 may be involved in cell proliferation and migration by PI3K/Akt/mTOR signaling pathway. Therefore, blocking B7-H4 signaling might be a novel treatment strategy for CRC.
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Affiliation(s)
- Chun Li
- Department of Pathology, Beihua University Faculty of Medicine, No. 3999 Binjiang East Road, Jilin, 132013, Jilin, People's Republic of China
| | - Yudong Zhan
- Department of Pathology, Beihua University Faculty of Medicine, No. 3999 Binjiang East Road, Jilin, 132013, Jilin, People's Republic of China
- Department of Pathology, Jingmen No. 1 People's Hospital, Jingmen, 448000, Hubei, People's Republic of China
| | - Xuzhe Ma
- Department of Pathology, Beihua University Faculty of Medicine, No. 3999 Binjiang East Road, Jilin, 132013, Jilin, People's Republic of China
| | - Hui Fang
- Department of Pathology, Beihua University Faculty of Medicine, No. 3999 Binjiang East Road, Jilin, 132013, Jilin, People's Republic of China
| | - Xiaodong Gai
- Department of Pathology, Beihua University Faculty of Medicine, No. 3999 Binjiang East Road, Jilin, 132013, Jilin, People's Republic of China.
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Zhou L, Ruan M, Liu Y, Zhu Y, Fu D, Wu K, Zhang Q. B7H4 expression in tumor cells impairs CD8 T cell responses and tumor immunity. Cancer Immunol Immunother 2020; 69:163-174. [PMID: 31848656 PMCID: PMC7000514 DOI: 10.1007/s00262-019-02451-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Accepted: 12/09/2019] [Indexed: 12/04/2022]
Abstract
B7 homolog 4 (B7H4) is considered a negative regulator of immune responses, but the immunoregulatory role of B7H4 in the tumor microenvironment is not clear. Here, we assessed B7H4 expression cell types in human breast cancer tissues and addressed its potential mechanisms in the CD8 T cell immune response. The results from flow cytometry and immunohistochemistry demonstrated that B7H4 was highly expressed in 26 out of 30 (86.7%) breast invasive ductal carcinomas, and B7H4 surface expression on tumor cells was inversely correlated with CD8 T lymphocytes infiltration (p < 0.0001). In vivo, B7H4-overexpressing tumor cells showed enhanced tumor growth in immunocompetent mice with impaired CD8 T cell infiltration of the tumor. Further investigation showed that activation and expansion of CD8 T cells within the lymph nodes were suppressed in B7H4-overexpessing tumor-bearing mice. An in vitro killing assay showed that the cytotoxicity of CD8 T cells was inhibited in B7H4-overexpressing tumor cells. These findings suggest that B7H4 in tumor cells is a negative regulator of CD8 T cell activation, expansion and cytotoxicity, indicating that tumor cell-associated B7H4 might be a target for T cell-based cancer immunotherapy.
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Affiliation(s)
- Linlin Zhou
- Institute of Immunotherapy, Fujian Medical University, No. 1 Xuefu North Road, Shangjie Town, Minhou County, Fuzhou, 350122, China
| | - Mei Ruan
- Institute of Immunotherapy, Fujian Medical University, No. 1 Xuefu North Road, Shangjie Town, Minhou County, Fuzhou, 350122, China
| | - Ying Liu
- Institute of Immunotherapy, Fujian Medical University, No. 1 Xuefu North Road, Shangjie Town, Minhou County, Fuzhou, 350122, China
| | - Yanyang Zhu
- Institute of Immunotherapy, Fujian Medical University, No. 1 Xuefu North Road, Shangjie Town, Minhou County, Fuzhou, 350122, China
| | - Deqiang Fu
- Institute of Immunotherapy, Fujian Medical University, No. 1 Xuefu North Road, Shangjie Town, Minhou County, Fuzhou, 350122, China
| | - Kunlin Wu
- The First Affiliated Hospital of Fujian Medical University, No. 20 Chating Middle Road, Fuzhou, 350005, China
| | - Qiuyu Zhang
- The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China.
- Institute of Immunotherapy, Fujian Medical University, No. 1 Xuefu North Road, Shangjie Town, Minhou County, Fuzhou, 350122, China.
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Wang JY, Wang WP. B7-H4, a promising target for immunotherapy. Cell Immunol 2019; 347:104008. [PMID: 31733822 DOI: 10.1016/j.cellimm.2019.104008] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2019] [Revised: 10/23/2019] [Accepted: 11/02/2019] [Indexed: 02/07/2023]
Abstract
The coinhibitory molecule B7-H4, an important member of the B7 family, is abnormally expressed in tumors, inflammation and autoimmune diseases. B7-H4 negatively regulates T cell immune response and promotes immune escape by inhibiting the proliferation, cytokine secretion, and cell cycle of T cells. Moreover, B7-H4 plays an extremely important role in tumorigenesis and tumor development including cell proliferation, invasion, metastasis, anti-apoptosis, etc. In addition, B7-H4 has the other biological functions, such as protection against type 1 diabetes (T1D) and islet cell transplantation. Therefore, B7-H4 has been identified as a novel marker or a therapeutic target for the treatment of tumors, inflammation, autoimmune diseases, and organ transplantation. Here, we summarized the expression profiles, physiological and pathological functions, and regulatory mechanisms of B7-H4, the signaling pathways involved, as well as B7-H4-based immunotherapy.
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Affiliation(s)
- Jia-Yu Wang
- Center for Drug Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China
| | - Wei-Peng Wang
- Center for Drug Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China.
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Chapoval AI, Chapoval SP, Shcherbakova NS, Shcherbakov DN. Immune Checkpoints of the B7 Family. Part 2. Representatives of the B7 Family B7-H3, B7-H4, B7-H5, B7-H6, B7-H7, and ILDR2 and Their Receptors. RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY 2019. [DOI: 10.1134/s1068162019050091] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Dong L, Xie L, Li M, Dai H, Wang X, Wang P, Zhang Q, Liu W, Hu X, Zhao M. Downregulation of B7-H4 suppresses tumor progression of hepatocellular carcinoma. Sci Rep 2019; 9:14854. [PMID: 31619714 PMCID: PMC6795893 DOI: 10.1038/s41598-019-51253-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2018] [Accepted: 09/28/2019] [Indexed: 01/13/2023] Open
Abstract
B7-H4, as a member of the B7 superfamily, was overexpressed in various types of cancers. However, the effects of B7-H4 on the aggressiveness of HCC and the underlying mechanisms have not yet been fully explored. For this purpose, B7-H4 expression was detected by Flow cytometry and Western blotting, it was highly expressed in several HCC cell lines but not in normal LO2 cell line. Knockdown B7-H4 expression induced HCC cells apoptosis by flow cytometry and colony formation assays and increased several apoptosis-related proteins, including survivin, cleaved caspase-3, cleaved caspase-7, and Bax, while the pro-growth protein survivin was reduced. Then the proliferation and cell cycle were suppressed after treated by siB7-H4. Moreover, the level of B7-H4 was significantly correlated with cell migration. In vivo, intra-tumor injection of siRNA targeting B7-H4 can significantly inhibited the growth of HepG2 cells in nude mice. Finally, regions of interest were manually traced on T1WI, T2WI, DWI and ADC of MR images. ADC values were increased in HCC xenografts after B7-H4 siRNA treatment. These data indicated that downregulation of B7-H4 suppressed the proliferation and migration and promoted apoptosis in vitro and in vivo. Blocking the B7-H4 channel might be a potential therapeutic strategy for HCC.
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Affiliation(s)
- Lijie Dong
- Department of Imaging, Binzhou Medical University, Binzhou, Shandong, 264003, P.R. China.,Department of Radiology, Binzhou Medical University Hospital, Binzhou, Shandong, 256603, P.R. China
| | - Lulu Xie
- Department of Imaging, Binzhou Medical University, Binzhou, Shandong, 264003, P.R. China
| | - Minjing Li
- Medicine & Pharmacy Research Center, Binzhou Medical University, Yantai, Shandong, 264003, P.R. China
| | - Hanhan Dai
- Department of Imaging, Binzhou Medical University, Binzhou, Shandong, 264003, P.R. China
| | - Xia Wang
- Department of Oral Pathology, Binzhou Medical University, Yantai, Shandong, 264003, P.R. China
| | - Peiyuan Wang
- Department of Imaging, Binzhou Medical University, Binzhou, Shandong, 264003, P.R. China
| | - Qiang Zhang
- Medicine & Pharmacy Research Center, Binzhou Medical University, Yantai, Shandong, 264003, P.R. China
| | - Wei Liu
- Department of Imaging, Binzhou Medical University, Binzhou, Shandong, 264003, P.R. China
| | - Xuemei Hu
- Department of Immunology, Binzhou Medical University, Yantai, Shandong, 264003, P.R. China.
| | - Mingdong Zhao
- Department of Imaging, Binzhou Medical University, Binzhou, Shandong, 264003, P.R. China.
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Qi ZJ, Yu D, Chen CH, Jiang H, Li R, Kang YM. The prognostic value of B7H1 and B7H4 expression in pancreatic cancer: A meta-analysis. Int J Biol Markers 2019; 34:373-380. [PMID: 31608800 DOI: 10.1177/1724600819881147] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
OBJECTIVE The clinical implications of B7H1 and B7H4 in pancreatic cancer have been described however, the prognostic significance of these genes in pancreatic cancer patients remains inconclusive. The aim of the present study was to evaluate the prognostic role of B7H1 and B7H4 in pancreatic cancer patients. METHODS Electronic databases (PubMed, EMBASE, and the Cochrane Library) were searched for relevant articles published before May 2019. Meta-analyses were performed by pooling the hazard ratios (HRs) between overall survival or cancer-specific survival and high or low expression of B7H1/B7H4 in pancreatic cancer patients. Subgroup and sensitivity analyses were performed, and sources of variabilities were explored by performing meta-regression. RESULTS Sixteen studies (1434 patients' data) were included. Compared with low expression, high expression of B7H1 was associated with significantly poor overall survival (HR 1.92 (95% confidence interval (CI) 1.35, 2.74); P<0.001) and cancer-specific survival (HR 2.46 (95% CI 1.55, 3.90); P<0.001). High expression of B7H4 also predicted poor overall survival (HR 2.38 (95% CI 1.89, 3.00); P<0.001). In subgroup analyses, a significant association between B7H1 and overall survival was observed for trials conducted in China (HR 2.08 (95% CI 1.29, 3.34)) but not in Japan (HR 1.98 (95% CI 1.33, 2.96)); or in studies with <50% patients having high expression (HR 2.02 (95% CI 1.40, 2.91)) but not in studies with >50% patients with high expression (HR 1.40 (95% CI 0.87, 2.26)). CONCLUSION The current study suggests that high B7H1 and B7H4 expression is associated with a poor prognosis in pancreatic cancer patients.
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Affiliation(s)
- Zi-Juan Qi
- Department of Pathology, Nangang Brach, Heilongjiang Provincial Hospital, Harbin, Heilongjiang, China
| | - Dan Yu
- Division III, Department of Gastroenterology, Nangang Brach, Heilongjiang Provincial Hospital, Harbin, Heilongjiang, China
| | - Chun-Hong Chen
- Division III, Department of Oncology, General Hospital of Heilongjiang Province Land Reclamation Bureau, Harbin, Heilongjiang, China
| | - Hong Jiang
- Department of Pathology, Nangang Brach, Heilongjiang Provincial Hospital, Harbin, Heilongjiang, China
| | - Ran Li
- Department of Pediatrics, Harbin Red Cross Central Hospital, Harbin, Heilongjiang, China
| | - Yong-Ming Kang
- Division III, Department of Gastroenterology, Nangang Brach, Heilongjiang Provincial Hospital, Harbin, Heilongjiang, China
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Saha A, Taylor PA, Lees CJ, Panoskaltsis-Mortari A, Osborn MJ, Feser CJ, Thangavelu G, Melchinger W, Refaeli Y, Hill GR, Munn DH, Murphy WJ, Serody JS, Maillard I, Kreymborg K, van den Brink M, Dong C, Huang S, Zang X, Allison JP, Zeiser R, Blazar BR. Donor and host B7-H4 expression negatively regulates acute graft-versus-host disease lethality. JCI Insight 2019; 4:127716. [PMID: 31578305 DOI: 10.1172/jci.insight.127716] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2019] [Accepted: 08/23/2019] [Indexed: 12/30/2022] Open
Abstract
B7-H4 is a negative regulatory B7 family member. We investigated the role of host and donor B7-H4 in regulating acute graft-versus-host disease (GVHD). Allogeneic donor T cells infused into B7-H4-/- versus WT recipients markedly accelerated GVHD-induced lethality. Chimera studies pointed toward B7-H4 expression on host hematopoietic cells as more critical than parenchymal cells in controlling GVHD. Rapid mortality in B7-H4-/- recipients was associated with increased donor T cell expansion, gut T cell homing and loss of intestinal epithelial integrity, increased T effector function (proliferation, proinflammatory cytokines, cytolytic molecules), and reduced apoptosis. Higher metabolic demands of rapidly proliferating donor T cells in B7-H4-/- versus WT recipients required multiple metabolic pathways, increased extracellular acidification rates (ECARs) and oxygen consumption rates (OCRs), and increased expression of fuel substrate transporters. During GVHD, B7-H4 expression was upregulated on allogeneic WT donor T cells. B7-H4-/- donor T cells given to WT recipients increased GVHD mortality and had function and biological properties similar to WT T cells from allogeneic B7-H4-/- recipients. Graft-versus-leukemia responses were intact regardless as to whether B7-H4-/- mice were used as hosts or donors. Taken together, these data provide new insights into the negative regulatory processes that control GVHD and provide support for developing therapeutic strategies directed toward the B7-H4 pathway.
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Affiliation(s)
- Asim Saha
- Masonic Cancer Center and Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, Minnesota, USA
| | - Patricia A Taylor
- Masonic Cancer Center and Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, Minnesota, USA
| | - Christopher J Lees
- Masonic Cancer Center and Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, Minnesota, USA
| | - Angela Panoskaltsis-Mortari
- Masonic Cancer Center and Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, Minnesota, USA
| | - Mark J Osborn
- Masonic Cancer Center and Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, Minnesota, USA
| | - Colby J Feser
- Masonic Cancer Center and Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, Minnesota, USA
| | - Govindarajan Thangavelu
- Masonic Cancer Center and Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, Minnesota, USA
| | - Wolfgang Melchinger
- Department of Hematology, Oncology, and Stem-Cell Transplantation, Freiburg University Medical Center, Albert Ludwigs University Freiburg, Freiburg, Germany
| | - Yosef Refaeli
- Department of Dermatology, University of Colorado, Aurora, Colorado, USA
| | - Geoffrey R Hill
- Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washington, USA
| | - David H Munn
- Department of Pediatrics, Georgia Health Sciences University, Augusta, Georgia, USA
| | - William J Murphy
- Department of Dermatology, UC Davis School of Medicine, Sacramento, California, USA
| | - Jonathan S Serody
- Department of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Ivan Maillard
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Katharina Kreymborg
- Department of Immunology and Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Marcel van den Brink
- Department of Immunology and Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Chen Dong
- Institute for Immunology and School of Medicine, Tsinghua University, Beijing, China
| | - Shuyu Huang
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA
| | - Xingxing Zang
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA
| | - James P Allison
- Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Robert Zeiser
- Department of Hematology, Oncology, and Stem-Cell Transplantation, Freiburg University Medical Center, Albert Ludwigs University Freiburg, Freiburg, Germany
| | - Bruce R Blazar
- Masonic Cancer Center and Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, Minnesota, USA
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Genova C, Boccardo S, Mora M, Rijavec E, Biello F, Rossi G, Tagliamento M, Dal Bello MG, Coco S, Alama A, Vanni I, Barletta G, Bianchi R, Maggioni C, Bruzzi P, Grossi F. Correlation between B7-H4 and Survival of Non-Small-Cell Lung Cancer Patients Treated with Nivolumab. J Clin Med 2019; 8:jcm8101566. [PMID: 31581482 PMCID: PMC6832616 DOI: 10.3390/jcm8101566] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Accepted: 09/24/2019] [Indexed: 12/26/2022] Open
Abstract
Reliable predictors of benefit from immune checkpoint inhibitors in non-small-cell lung cancer (NSCLC) are still limited. We aimed to evaluate the association between the expression of selected molecules involved in immune response and clinical outcomes in NSCLC patients receiving nivolumab. In our study, the outcomes of 46 NSCLC patients treated with nivolumab in second or subsequent lines (Nivolumab Cohort) were compared with the expression of PD-L1, PD-L2, PD-1, B7-H3, and B7-H4 assessed by immunohistochemistry (IHC). Samples from 17 patients (37.0%) in the Nivolumab Cohort were positive for B7-H4 expression. At univariate analyses, only B7-H4 expression was associated with significantly decreased progression-free survival (PFS; 1.7 vs. 2.0 months; p = 0.026) and with a disadvantage in terms of overall survival (OS) close to statistical significance (4.4 vs. 9.8 months; p = 0.064). At multivariate analyses, B7-H4 expression was significantly associated with decreased PFS (hazard ratio (HR) = 2.28; p = 0.021) and OS (HR = 2.38; p = 0.022). Subsequently, B7-H4 expression was compared with clinical outcomes of 27 NSCLC patients receiving platinum-based chemotherapy (Chemotherapy Cohort), but no significant association was observed. Our results suggest a negative predictive role of B7-H4 in a population of NSCLC treated with immune checkpoint inhibitors, which deserves further research.
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Affiliation(s)
- Carlo Genova
- Lung Cancer Unit, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132 Genoa, Italy.
| | - Simona Boccardo
- Lung Cancer Unit, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132 Genoa, Italy.
| | - Marco Mora
- Pathology Unit, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132 Genoa, Italy.
| | - Erika Rijavec
- Medical Oncology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Via Francesco Sforza, 28, 20122 Milan, Italy.
| | - Federica Biello
- Oncology Unit, Ospedale Maggiore della Carità, Corso Mazzini 18, 28100 Novara, Italy.
| | - Giovanni Rossi
- Lung Cancer Unit, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132 Genoa, Italy.
| | - Marco Tagliamento
- Lung Cancer Unit, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132 Genoa, Italy.
| | - Maria Giovanna Dal Bello
- Lung Cancer Unit, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132 Genoa, Italy.
| | - Simona Coco
- Lung Cancer Unit, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132 Genoa, Italy.
| | - Angela Alama
- Lung Cancer Unit, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132 Genoa, Italy.
| | - Irene Vanni
- Lung Cancer Unit, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132 Genoa, Italy.
| | - Giulia Barletta
- Lung Cancer Unit, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132 Genoa, Italy.
| | - Rita Bianchi
- Pathology Unit, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132 Genoa, Italy.
| | - Claudia Maggioni
- Lung Cancer Unit, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132 Genoa, Italy.
| | - Paolo Bruzzi
- Department of Epidemiology, Biostatistics and Clinical Trials, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132 Genoa, Italy.
| | - Francesco Grossi
- Medical Oncology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Via Francesco Sforza, 28, 20122 Milan, Italy.
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Kaur G, Janakiram M. B7x-from bench to bedside. ESMO Open 2019; 4:e000554. [PMID: 31555486 PMCID: PMC6735664 DOI: 10.1136/esmoopen-2019-000554] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Revised: 08/12/2019] [Accepted: 08/14/2019] [Indexed: 01/30/2023] Open
Abstract
B7x is an immune checkpoint molecule which belongs to the B7 family of ligands which includes PD-L1, PD-L2, B7-H3 and HHLA2. B7x belongs to the Immunoglobulin superfamily and its protein structure is similar to other members with a N terminus peptide, IgV and IgC like extracellular domain with four cysteine residues. Its receptor is yet to be identified. B7x inhibits T cell proliferation and expansion by IL-2 dependent and non-IL-2 dependent pathways. Even though high levels of B7x mRNA can be detected in most tissues its protein expression is highly limited suggesting significant post translational control. In vivo data, show that B7x plays an important role in limiting autoimmunity in the peripheral tissues and fine-tuning autoimmune responses. B7x is highly expressed in various cancers and in prostate cancer its expression is corelated with poorer outcomes. Local production of IL-6 and IL-10 in various cancers promotes B7x expression and tumor immune evasion. B7x is especially expressed in PD-L1 negative tumors suggesting that this may be an important method of immune evasion in these tumors. Currently drug development, targeting B7x through various mechanisms including monoclonal antibodies and antibody drug conjugates are in development in cancers and increasing B7x expression with fusion proteins in autoimmune diseases is underway.
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Affiliation(s)
- Gurbakhash Kaur
- Department of Medical Oncology, Albert Einstein College of Medicine, New York city, New York, USA
| | - Murali Janakiram
- Department of Medical Oncology, Albert Einstein College of Medicine, New York city, New York, USA.,Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA
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Guo L, Liu Z, Zhang Y, Quan Q, Huang L, Xu Y, Cao L, Zhang X. Association of increased B7 protein expression by infiltrating immune cells with progression of gastric carcinogenesis. Medicine (Baltimore) 2019; 98:e14663. [PMID: 30813210 PMCID: PMC6407991 DOI: 10.1097/md.0000000000014663] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
B7 negative costimulatory molecules are a group of molecules associated with the occurrence, development, and therapy of cancers. Here, we aimed to determine the clinical significance of PD-L1, B7-H3, and B7-H4 and their expression in CD8 and CD68 positive cells at different stages of gastric carcinogenesis.We detected PD-L1, B7-H3, B7-H4, CD8, and CD68 expression in samples by immunohistochemical staining of 62 chronic superficial gastritis (CSG) samples, 72 chronic atrophic gastritis (CAG) samples, 68 low-grade intraepithelial neoplasia (LIN) samples, 65 high-grade intraepithelial neoplasia (HIN) samples obtained from gastroscopic biopsies and 50 gastric adenocarcinoma (GA) samples obtained from surgical resections. Then we statistically analyzed the expression differences and correlations.Our results indicated that B7 and CD68 expression on infiltrating immune cells was associated with disease progression. However, infiltration of CD8+ cells decreased with disease progression. B7-H3 expression was markedly enhanced at neoplasia and GA stages. B7-H3 in tumor cells was negatively correlated with CD8-expressing cells. Conversely, B7-H3 expression in tumor-infiltrating immune cells was positively correlated with CD68-expressing cells. B7-H4 expression was found in the cell membrane at the stages of gastritis and low-grade neoplasia and was gradually expressed in the cytoplasm at high-grade neoplasia and GA stages. High B7-H4 expression in infiltrating immune cells was also significantly associated with lower CD8-positive and higher CD68-positive cell densities.Increased B7 protein expression by infiltrating immune cells was associated with disease progression, and specifically, the level of B7-H3 expression and localization of B7-H4 expression differed significantly among different stages of gastric carcinogenesis.
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Affiliation(s)
- Lingchuan Guo
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University; Department of Pathology, The First Affiliated Hospital of Soochow University
| | - Zhiju Liu
- Department of Pathology, The First Affiliated Hospital of Soochow University
| | - Yun Zhang
- Department of Pathology, The First Affiliated Hospital of Soochow University
| | - Qiuying Quan
- Department of Pathology, The First Affiliated Hospital of Soochow University
| | | | - Yunyun Xu
- Institute of Pediatric Medicine, Children's Hospital of Soochow University
| | - Lei Cao
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University
| | - Xueguang Zhang
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University; Jiangsu Key Laboratory of Clinical Immunology, Soochow University; Jiangsu Key Laboratory of Gastrointestinal tumor Immunology, Suzhou, PR China
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Co-signal Molecules in T-Cell Activation. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1189:3-23. [DOI: 10.1007/978-981-32-9717-3_1] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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Wang L, Yang C, Liu XB, Wang L, Kang FB. B7-H4 overexpression contributes to poor prognosis and drug-resistance in triple-negative breast cancer. Cancer Cell Int 2018; 18:100. [PMID: 30008617 PMCID: PMC6044050 DOI: 10.1186/s12935-018-0597-9] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2018] [Accepted: 07/06/2018] [Indexed: 11/20/2022] Open
Abstract
Background The expression of the immunoregulatory protein B7-H4 has been reported in many types of cancer, including breast cancer. However, its role in triple-negative breast cancer (TNBC), especially its correlation with patients’ prognosis and chemoresistance remains unclear. Methods The expression of B7-H4 in TNBC tissues and cell lines were measured with Real-Time PCR and western blotting. 65 cases of TNBC tissue samples and adjacent non-tumor tissue samples were analyzed by immunochemistry to demonstrate the correlation between the B7-H4 expression and clinicopathological characteristics. In vitro studies assessed mAb MIH43 alone and in combination with transfecting B7-H4 siRNA on the growth of chemosensitive and chemoresistant TNBC cell lines by CCK-8 and apoptotic enzyme-linked immunosorbent assay (ELISA). Results B7-H4 expression was detected positive in 59 of 65 (90.8%) different stage TNBC patients, especially in the samples of recurrence TNBC patients after receiving neoadjuvant chemotherapy treatment. Survival curves showed that patients with B7-H4 overexpression had significantly shorter survival and recurrence time than those with low B7-H4 expression (p < 0.005). Univariate and multivariate COX regression analysis demonstrated that B7-H4 was an independent predictor for advanced tumor stage. The monoclonal antibody of B7-H4 has the potential anti-proliferative effects on inhibiting the chemoresistant TNBC cell lines and increasing the sensitivity of TNBC cell lines to doxorubicin, paclitaxel or carboplatin. RNAi-mediated silencing of B7-H4 in TNBC cells enhanced drug-induced apoptosis via inhibiting PTEN/PI3K/AKT pathway, whereas reexpression of B7-H4 in B7-H4 knockdown and low B7-H4 expressing cells increased the phosphorylation of PI3K and AKT along with restoration of PETN expression. Conclusions Our data show that B7-H4 is a biomarker indicative of a poor prognosis in TNBC patients and at least partially downregulated in chemoresistance via PTEN/PI3K/AKT pathway. Targeting B7-H4 might provide an attractive therapeutic approach specifically for TNBC patients. Electronic supplementary material The online version of this article (10.1186/s12935-018-0597-9) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Ling Wang
- 1Department of Orthopedic Oncology, the Third Hospital of Hebei Medical University, Shijiazhuang, Hebei People's Republic of China
| | - Chao Yang
- 2Department of General Surgery, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei People's Republic of China
| | - Xin-Bo Liu
- 3Department of Thoracic Surgery, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei People's Republic of China
| | - Li Wang
- Department of Pathology, the Fourth Hospital of Shijiazhuang, Shijiazhuang, China
| | - Fu-Biao Kang
- 5Department of Liver Diseases, Bethune International Peace Hospital, Shijiazhuang, Hebei People's Republic of China
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Podojil JR, Chiang MY, Ifergan I, Copeland R, Liu LN, Maloveste S, Langermann S, Liebenson D, Balabanov R, Chi H, Chen L, Vignali DAA, Miller SD. B7-H4 Modulates Regulatory CD4 + T Cell Induction and Function via Ligation of a Semaphorin 3a/Plexin A4/Neuropilin-1 Complex. THE JOURNAL OF IMMUNOLOGY 2018; 201:897-907. [PMID: 29898965 DOI: 10.4049/jimmunol.1700811] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/06/2017] [Accepted: 05/21/2018] [Indexed: 11/19/2022]
Abstract
The potent immune regulatory function of an agonistic B7-H4-Ig fusion protein (B7-H4Ig) has been demonstrated in multiple experimental autoimmune models; however, the identity of a functional B7-H4 receptor remained unknown. The biological activity of B7-H4 is associated with decreased inflammatory CD4+ T cell responses as supported by a correlation between B7-H4-expressing tumor-associated macrophages and Foxp3+ T cells within the tumor microenvironment. Recent data indicate that members of the semaphorin (Sema)/plexin/neuropilin (Nrp) family of proteins both positively and negatively modulate immune cell function. In this study, we show that B7-H4 binds the soluble Sema family member Sema3a. Additionally, B7-H4Ig-induced inhibition of inflammatory CD4+ T cell responses is lost in both Sema3a functional mutant mice and mice lacking Nrp-1 expression in Foxp3+ T cells. These findings indicate that B7-H4Ig binds to Sema3a, which acts as a functional bridge to stimulate an Nrp-1/Plexin A4 heterodimer to form a functional immunoregulatory receptor complex resulting in increased levels of phosphorylated PTEN and enhanced regulatory CD4+ T cell number and function.
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Affiliation(s)
- Joseph R Podojil
- Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611
| | - Ming-Yi Chiang
- Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611
| | - Igal Ifergan
- Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611
| | | | | | | | | | | | | | - Hongbo Chi
- Immunology Department, St. Jude Children's Research Hospital, Memphis, TN 38105
| | - Lieping Chen
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06510
| | - Dario A A Vignali
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15262; and.,Tumor Microenvironment Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15232
| | - Stephen D Miller
- Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611;
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Mach P, Nolte-Boenigk L, Droste L, Fox L, Frank M, Schmidt B, Herse F, Verlohren S, Wicherek L, Iannaccone A, Birdir C, Andrikos D, Kimmig R, Gellhaus A, Köninger A. Soluble B7-H4 blood serum levels are elevated in women at high risk for preeclampsia in the first trimester, as well as in patients with confirmed preeclampsia. Am J Reprod Immunol 2018; 80:e12988. [PMID: 29797540 DOI: 10.1111/aji.12988] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Accepted: 05/06/2018] [Indexed: 12/23/2022] Open
Abstract
PROBLEM B7-H4 negatively regulates T-cell-mediated immunity and might play an important role in preeclampsia (PE). Here, we have investigated the association between PE and maternal soluble B7-H4 (sB7-H4) serum levels and B7-H4 mRNA expression in the placenta. METHOD OF STUDY Maternal serum levels of sB7-H4 were determined by enzyme-linked immunosorbent assay in women between 11 and 13 weeks' gestation with elevated risk for PE (n = 48) and women without elevated risk for PE (n = 47). In the third trimester, sB7-H4 serum levels (n = 166) and B7-H4 mRNA expression in the placenta (n = 54) were determined in women with early-onset PE, late-onset PE, fetal growth restriction (FGR), and in healthy controls. RESULTS In the first trimester, significant higher levels of sB7-H4 were detected in women at elevated risk for PE compared to women without risk for PE (P < .0001). sB7-H4 has some predictive ability to identify cases with an elevated risk of developing PE with area under the curve (AUC) value of 0.88 (95% CI 0.8-0.94). Using a specificity of 90.0% led to a sensitivity of 47.9% and a threshold of 3.63 ng/mL. In the third trimester, the highest serum levels of sB7-H4 and B7-H4 mRNA expression in the placenta were observed in early-onset PE. Significant higher serum levels of sB7-H4 and B7-H4 mRNA expression in the placenta were observed in women with early-onset PE (P = .01 and P = .006, respectively) and late-onset PE (P = .03 and P = .004, respectively) compared to healthy controls, but not compared to FGR. CONCLUSION sB7-H4 is involved in the regulation of immune tolerance in women with PE in the third trimester. In the first trimester of pregnancy, sB7-H4 might serve as a predictive immunological biomarker for women who are at elevated risk of developing PE.
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Affiliation(s)
- Pawel Mach
- Department of Obstetrics and Gynecology, University Hospital of Essen, Essen, Germany
| | - Luisa Nolte-Boenigk
- Department of Obstetrics and Gynecology, University Hospital of Essen, Essen, Germany
| | - Leonie Droste
- Department of Obstetrics and Gynecology, University Hospital of Essen, Essen, Germany
| | - Laura Fox
- Department of Obstetrics and Gynecology, University Hospital of Essen, Essen, Germany
| | - Mirjam Frank
- Institute for Medical Informatics, Biometry and Epidemiology, University of Duisburg-Essen, Essen, Germany
| | - Boerge Schmidt
- Institute for Medical Informatics, Biometry and Epidemiology, University of Duisburg-Essen, Essen, Germany
| | - Florian Herse
- Charité Medical Faculty, Experimental and Clinical Research Center, a joint cooperation between the Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.,Berlin Institute of Health (BIH), Berlin, Germany
| | - Stefan Verlohren
- Department of Obstetrics, Charité University Medicine, Berlin, Germany
| | - Lukasz Wicherek
- Department of Gynecology and Oncology and Gynecological Nursing, Ludwik Rydygier Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland
| | - Antonella Iannaccone
- Department of Obstetrics and Gynecology, University Hospital of Essen, Essen, Germany
| | - Cahit Birdir
- Department of Obstetrics and Gynecology, University Hospital of Essen, Essen, Germany.,Medical Faculty, Department of Obstetrics and Gynecology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Dimitrios Andrikos
- Department of Obstetrics and Gynecology, University Hospital of Essen, Essen, Germany
| | - Rainer Kimmig
- Department of Obstetrics and Gynecology, University Hospital of Essen, Essen, Germany
| | - Alexandra Gellhaus
- Department of Obstetrics and Gynecology, University Hospital of Essen, Essen, Germany
| | - Angela Köninger
- Department of Obstetrics and Gynecology, University Hospital of Essen, Essen, Germany
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Ni L, Dong C. New B7 Family Checkpoints in Human Cancers. Mol Cancer Ther 2018; 16:1203-1211. [PMID: 28679835 DOI: 10.1158/1535-7163.mct-16-0761] [Citation(s) in RCA: 182] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2016] [Revised: 02/17/2017] [Accepted: 04/20/2017] [Indexed: 01/22/2023]
Abstract
T cells are the main effector cells in immune response against tumors. The activation of T cells is regulated by the innate immune system through positive and negative costimulatory molecules. Targeting immune checkpoint regulators such as programmed cell death 1 (PD-1)/PD-1 ligand 1 (PD-L1) and CTL antigen 4 (CTLA-4) has achieved notable benefit in a variety of cancers, which leads to multiple clinical trials with antibodies targeting the other related B7/CD28 family members. Recently, five new B7 family ligands, B7-H3, B7-H4, B7-H5, B7-H6, and B7-H7, were identified. Here we review recent understanding of new B7 family checkpoint molecules as they have come to the front of cancer research with the concept that tumor cells exploit them to escape immune surveillance. The aim of this article is to address the structure and expression of the new B7 family molecules as well as their roles in controlling and suppressing immune responses of T cells as well as NK cells. We also discuss clinical significance and contribution of these checkpoint expressions in human cancers. Mol Cancer Ther; 16(7); 1203-11. ©2017 AACR.
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Affiliation(s)
- Ling Ni
- Institute for Immunology and School of Medicine, Tsinghua University, Beijing, China.
| | - Chen Dong
- Institute for Immunology and School of Medicine, Tsinghua University, Beijing, China
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Song X, Shao Y, Gu W, Xu C, Mao H, Pei H, Jiang J. Prognostic role of high B7-H4 expression in patients with solid tumors: a meta-analysis. Oncotarget 2018; 7:76523-76533. [PMID: 27058425 PMCID: PMC5363528 DOI: 10.18632/oncotarget.8598] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2015] [Accepted: 03/28/2016] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND Recently, many studies have shown that B7-H4 exhibits altered expression in various cancers. We performed a meta-analysis to evaluate the prognostic role of B7-H4 expression in solid tumors. RESULTS Data from 18 observational studies and 2467 patients were summarized. An elevated baseline B7-H4 was significantly associated with worse OS (pooled HR = 1.79; 95% CI = 1.56-2.06). Differences across subgroups of tumor type, patients' ethnicity, analysis type, HR obtain method and cut-off value were not significant (PD = 0.313, PD = 0.716, PD = 0.896, PD = 0.290 and PD = 0.153, respectively). Furthermore, patients with high B7-H4 had a significantly shorter DFS (pooled HR = 2.12; 95%CI = 1.45-3.09). MATERIALS AND METHODS We searched PubMed, Embase and the Cochrane Library (last update by November 26, 2015) to identify studies assessing the effect of B7-H4 on survival of cancer patients. Pooled hazard ratios (HRs) for overall survival (OS) and disease-free survival (DFS) were estimated using fixed-effects models and random-effects models respectively. CONCLUSIONS This meta-analysis clarified that high B7-H4 expression in tissue was significantly associated with poor survival in patients with solid tumors. Future clinical studies are warranted to determine whether B7-H4 blockade has a favorable effect on disease recurrence and mortality.
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Affiliation(s)
- Xing Song
- Department of Radiation Oncology, The Third Affiliated Hospital of Soochow University, Changzhou 213003, People's Republic of China
| | - Yingjie Shao
- Department of Radiation Oncology, The Third Affiliated Hospital of Soochow University, Changzhou 213003, People's Republic of China
| | - Wendong Gu
- Department of Radiation Oncology, The Third Affiliated Hospital of Soochow University, Changzhou 213003, People's Republic of China
| | - Chao Xu
- Department of Laboratory, The Third Affiliated Hospital of Soochow University, Changzhou 213003, People's Republic of China
| | - Huihui Mao
- Department of Laboratory, The Third Affiliated Hospital of Soochow University, Changzhou 213003, People's Republic of China
| | - Honglei Pei
- Department of Radiation Oncology, The Third Affiliated Hospital of Soochow University, Changzhou 213003, People's Republic of China
| | - Jingting Jiang
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou 213003, People's Republic of China
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