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

Eswari Dodagatta-Marri; 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

doi:10.1016/j.celrep.2021.109309

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

Cell Rep. 2021 Jul 6;36(1):109309. doi: 10.1016/j.celrep.2021.109309.

Authors

Eswari Dodagatta-Marri¹, Hsiao-Yen Ma², Benjia Liang³, John Li², Dominique S Meyer¹, Szu-Ying Chen¹, Kai-Hui Sun², Xin Ren², Bahar Zivak⁴, Michael D Rosenblum⁴, Mark B Headley⁵, Lauren Pinzas¹, Nilgun I Reed², Joselyn S Del Cid², Byron C Hann¹, Sharon Yang⁶, Anand Giddabasappa⁷, Kavon Noorbehesht⁷, Bing Yang⁷, Joseph Dal Porto⁸, Tatsuya Tsukui², Kyle Niessen⁸, Amha Atakilit², Rosemary J Akhurst⁹, Dean Sheppard¹⁰

Affiliations

¹ Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
² Lung Biology Center, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
³ Lung Biology Center, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA; Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, Shandong, China.
⁴ Department of Dermatology, University of California, San Francisco, San Francisco, CA, USA.
⁵ Department of Pathology, University of California, San Francisco, San Francisco, CA, USA.
⁶ Comparative Medicine, Pfizer Inc., San Diego, CA, USA.
⁷ Oncology Research Unit, Pfizer Inc., Pearl River, NY, USA.
⁸ Pfizer Centers for Therapeutic Innovation, San Francisco, CA, USA.
⁹ Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA; Department of Anatomy, University of California, San Francisco, San Francisco, CA, USA. Electronic address: [email protected].
¹⁰ Lung Biology Center, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA. Electronic address: [email protected].

Abstract

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.

Keywords: CD8 T cells; TGFbeta; alphavbeta8; anti-tumor immunity; integrin.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antibodies, Neoplasm / immunology
CD4-Positive T-Lymphocytes / immunology
CD8-Positive T-Lymphocytes / immunology
CTLA-4 Antigen / immunology
Cell Line, Tumor
Cell Proliferation
Gene Expression Regulation, Neoplastic
Granzymes / metabolism
Immunity*
Immunotherapy*
Integrins / metabolism*
Interferon-gamma / metabolism
Lymphocyte Depletion
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Models, Biological*
Mutation / genetics
Neoplasms / genetics
Neoplasms / immunology*
Neoplasms / pathology
Neoplasms / therapy*
Signal Transduction
Smad3 Protein / metabolism
Survival Analysis
T-Lymphocytes / immunology*
T-Lymphocytes, Cytotoxic / immunology
Transforming Growth Factor beta / metabolism
Tumor Microenvironment / immunology
Tumor Necrosis Factor Receptor Superfamily, Member 9 / metabolism

Substances

Antibodies, Neoplasm
CTLA-4 Antigen
Integrins
Smad3 Protein
Transforming Growth Factor beta
Tumor Necrosis Factor Receptor Superfamily, Member 9
integrin alphavbeta8
Interferon-gamma
Granzymes

Abstract

Publication types

MeSH terms

Substances

Grants and funding