Using syngeneic mouse models, Dodagatta-Marri and Ma et al. showed the CD8+ T cell-dependent antitumor effects of the blocking antibody ADWA-11, which is specific for the TGFβ-activating integrin αvβ8. ADWA-11 therapy synergized with immuno- or radiotherapies, despite tumor cells lacking αvβ8. Treatment boosted intratumoral CD8+ T cell accumulation and expression of granzyme A, B, FasL, and IFNγ, and inhibited TGFβ signaling effector SMAD3. β8 mRNA expression was highest in CD4+CD25+Foxp3+ T cells, and ADWA-11 blocked their suppression of CD8+ T cell tumor killing in vitro. Knockout of β8 T cell expression mimicked ADWA-11’s antitumor effects in vivo.
Contributed by Paula Hochman
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.
Author Info: (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
Author Info: (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) Lung Biology Center, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA. (5) Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA. (6) Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA. (7) Lung Biology Center, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA. (8) Lung Biology Center, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA. (9) Department of Dermatology, University of California, San Francisco, San Francisco, CA, USA. (10) Department of Dermatology, University of California, San Francisco, San Francisco, CA, USA. (11) Department of Pathology, University of California, San Francisco, San Francisco, CA, USA. (12) Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA. (13) Lung Biology Center, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA. (14) Lung Biology Center, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA. (15) Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA. (16) Comparative Medicine, Pfizer Inc., San Diego, CA, USA. (17) Oncology Research Unit, Pfizer Inc., Pearl River, NY, USA. (18) Oncology Research Unit, Pfizer Inc., Pearl River, NY, USA. (19) Oncology Research Unit, Pfizer Inc., Pearl River, NY, USA. (20) Pfizer Centers for Therapeutic Innovation, San Francisco, CA, USA. (21) Lung Biology Center, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA. (22) Pfizer Centers for Therapeutic Innovation, San Francisco, CA, USA. (23) Lung Biology Center, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA. (24) 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. (25) Lung Biology Center, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA. Electronic address: dean.sheppard@ucsf.edu.
