Integrin αvβ8 on T cells suppresses anti-tumor immunity in multiple models and is a promising target for tumor immunotherapy

• DOI: 10.1016/j.celrep.2021.109309
• Publication Date: 2021-07-06T14:42:37Z
• Authors: Eswari Dodagatta-...; Hsiao-Yen Ma; Benjia Liang; John Li; Dominique S. Meyer; Szu-Ying Chen; Kai-Hui Sun; Xin Ren; Bahar Zivak; Michael D. Rosenblum; Mark B. Headley; Lauren Pinzas; Nilgun I. Reed; Joselyn S. Del Cid; Byron C. Hann; Sharon Yang; Anand Giddabasappa; Kavon Noorbehesht; Bing Yang; Joseph Dal Porto; Tatsuya Tsukui; Kyle Niessen; Amha Atakilit; Rosemary J. Akhurst; Dean Sheppard
• Keywords: CD4-Positive T-Lymphocytes; Male; Integrins; Cytotoxic; Antibodies, Neoplasm; T-Lymphocytes; CD8-Positive T-Lymphocytes; Inbred C57BL; Transgenic; Granzymes; Mice; Models; Transforming Growth Factor beta; Neoplasms; Tumor Microenvironment; 2.1 Biological and endogenous factors; CTLA-4 Antigen; Cancer; 0303 health sciences; Tumor; Tumor Necrosis Factor Receptor Superfamily; Biological Sciences; Colo-Rectal Cancer; 3. Good health; Gene Expression Regulation, Neoplastic; 5.1 Pharmaceuticals; TGFbeta; Immunotherapy; Signal Transduction; 610; Member 9; CD8 T cells; Mice, Transgenic; Models, Biological; Antibodies; Article; Lymphocyte Depletion; Cell Line; Vaccine Related; Interferon-gamma; 03 medical and health sciences; Cell Line, Tumor; Breast Cancer; Animals; Smad3 Protein; Cell Proliferation; Neoplastic; Immunity; Biological; Survival Analysis; Mice, Inbred C57BL; Gene Expression Regulation; alphavbeta8; Mutation; Women's Health; Neoplasm; Immunization; Digestive Diseases

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.