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

Autor:	Dodagatta-Marri E; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA., Ma HY; Lung Biology Center, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA., Liang B; 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., Li J; Lung Biology Center, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA., Meyer DS; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA., Chen SY; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA., Sun KH; Lung Biology Center, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA., Ren X; Lung Biology Center, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA., Zivak B; Department of Dermatology, University of California, San Francisco, San Francisco, CA, USA., Rosenblum MD; Department of Dermatology, University of California, San Francisco, San Francisco, CA, USA., Headley MB; Department of Pathology, University of California, San Francisco, San Francisco, CA, USA., Pinzas L; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA., Reed NI; Lung Biology Center, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA., Del Cid JS; Lung Biology Center, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA., Hann BC; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA., Yang S; Comparative Medicine, Pfizer Inc., San Diego, CA, USA., Giddabasappa A; Oncology Research Unit, Pfizer Inc., Pearl River, NY, USA., Noorbehesht K; Oncology Research Unit, Pfizer Inc., Pearl River, NY, USA., Yang B; Oncology Research Unit, Pfizer Inc., Pearl River, NY, USA., Dal Porto J; Pfizer Centers for Therapeutic Innovation, San Francisco, CA, USA., Tsukui T; Lung Biology Center, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA., Niessen K; Pfizer Centers for Therapeutic Innovation, San Francisco, CA, USA., Atakilit A; Lung Biology Center, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA., Akhurst RJ; 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: rosemary.akhurst@ucsf.edu., Sheppard D; Lung Biology Center, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA. Electronic address: dean.sheppard@ucsf.edu.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2021 Jul 06; Vol. 36 (1), pp. 109309.
DOI:	10.1016/j.celrep.2021.109309
Abstrakt:	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. Competing Interests: Declaration of interests D.S. and R.J.A. were funded by a grant from the joint UCSF-Pfizer CTI. S.Y., A.G., K. Noorbehesht, B.Y., K. Niessen, and J.D.P. were employees of Pfizer. UCSF and Pfizer have filed a joint patent covering the use of a humanized version of ADWA-11 for cancer immunotherapy. (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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