Integrin αvβ8 on T cells suppresses anti-tumor immunity in multiple models and is a promising target for tumor immunotherapy
| Autor: | Rosemary J. Akhurst, Bahar Zivak, Eswari Dodagatta-Marri, John T. Li, Niessen Kyle Steven, Bing Yang, Szu-Ying Chen, Joselyn S. Del Cid, Dean Sheppard, Michael Rosenblum, Benjia Liang, Dominique S. Meyer, Tatsuya Tsukui, Anand Giddabasappa, Hsiao-Yen Ma, Lauren Pinzas, Sharon Yang, Mark B. Headley, Kai-Hui Sun, Nilgun Isik Reed, Xin Ren, Joseph Dal Porto, Kavon Noorbehesht, Amha Atakilit, Byron Hann |
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| Rok vydání: | 2020 |
| Předmět: |
CD4-Positive T-Lymphocytes
Male Integrins Antibodies Neoplasm medicine.medical_treatment T-Lymphocytes Mice Transgenic CD8-Positive T-Lymphocytes Models Biological General Biochemistry Genetics and Molecular Biology Granzymes Lymphocyte Depletion Article Interferon-gamma Mice Tumor Necrosis Factor Receptor Superfamily Member 9 Cancer immunotherapy Transforming Growth Factor beta Cell Line Tumor Neoplasms medicine Tumor Microenvironment Cytotoxic T cell Animals CTLA-4 Antigen IL-2 receptor Smad3 Protein Cell Proliferation Chemistry Immunity Cancer Immunotherapy medicine.disease Survival Analysis Granzyme B Gene Expression Regulation Neoplastic Mice Inbred C57BL Mutation Cancer research CD8 Transforming growth factor Signal Transduction T-Lymphocytes Cytotoxic |
| Zdroj: | Cell reports |
| ISSN: | 2211-1247 |
| Popis: | SUMMARY αvβ8 integrin, a key activator of transforming growth factor β (TGF-β), inhibits anti-tumor immunity. We show that a potent blocking monoclonal antibody against αvβ8 (ADWA-11) causes growth suppression or complete regression in syngeneic models of squamous cell carcinoma, mammary cancer, colon cancer, and prostate cancer, especially when combined with other immunomodulators or radiotherapy. αvβ8 is expressed at the highest levels in CD4+CD25+ T cells in tumors, and specific deletion of β8 from T cells is as effective as ADWA-11 in suppressing tumor growth. ADWA-11 increases expression of a suite of genes in tumor-infiltrating CD8+ T cells normally inhibited by TGF-β and involved in tumor cell killing, including granzyme B and interferon-γ. The in vitro cytotoxic effect of tumor CD8 T cells is inhibited by CD4+CD25+ cells, and this suppressive effect is blocked by ADWA-11. These findings solidify αvβ8 integrin as a promising target for cancer immunotherapy. Graphical abstract In brief TGF-β suppresses anti-tumor immunity. Dodagatta-Marri, Ma et al. show that the TGF-β-activating integrin αvβ8 is expressed on CD25+CD4+ tumor T cells and suppresses anti-tumor immunity by CD8+ T cells. Blocking this integrin enhances tumor cell killing and synergizes with multiple immune modulators or radiotherapy to induce long-term anti-tumor immunity. |
| Databáze: | OpenAIRE |
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