Integrin αvβ8 on T Cells is Responsible for Suppression of Anti-Tumor Immunity in Syngeneic Models and is a Promising Target for Tumor Immunotherapy

Abstract

The αvβ8 integrin is a key activator of transforming growth factor β(TGFβ), which has been shown to inhibit anti-tumor immunity. Previous work has suggested that αvβ8 on tumor cells could modulate tumor growth and responses to immune checkpoint blockade. We now show that a potent blocking monoclonal antibody against avb8 (ADWA-11) causes growth suppression or complete regression in syngeneic models of squamous cell carcinoma (CCK168), mammary cancer (EMT-6), colon cancer (CT26), and prostate cancer (TRAMPC2), especially when it is combined with other immunomodulators (anti-PD-1, anti-CTLA-4 or 4-1BB) or radiotherapy. αvβ8 is expressed on tumor cells in some of these models, but tumor cell expression of avb8 is not essential for the beneficial effects of ADWA-11 therapy. αvβ8 is consistently expressed at highest levels on CD4+CD25+ T cells within tumors, and specific deletion of Itgb8 from T cells is as effective as ADWA-11 in suppressing tumor growth. Treatment with ADWA-11 increases expression of a suite of genes in tumor infiltrating CD8+ T cells that are normally inhibited by TGFβ and are involved in tumor cell killing, including Granzyme B and Interferon-g. These findings solidify αvβ8 integrin as a promising target for cancer immunotherapy, even for tumors that do not express this integrin.