Regulatory T cells promote cancer immune-escape through integrin αvβ8-mediated TGF-β activation

Presence of TGFβ in the tumor microenvironment is one of the most relevant cancer immune-escape mechanisms. TGFβ is secreted in an inactive form, and its activation within the tumor may depend on different cell types and mechanisms than its production. Here we show in mouse melanoma and breast cancer models that regulatory T (Treg) cells expressing the β8 chain of αvβ8 integrin (Itgβ8) are the main cell type in the tumors that activates TGFβ, produced by the cancer cells and stored in the tumor micro-environment. Itgβ8 ablation in Treg cells impairs TGFβ signalling in intra-tumoral T lymphocytes but not in the tumor draining lymph nodes. Successively, the effector function of tumor infiltrating CD8(+) T lymphocytes strengthens, leading to efficient control of tumor growth. In cancer patients, anti-Itgβ8 antibody treatment elicits similar improved cytotoxic T cell activation. Thus, this study reveals that Treg cells work in concert with cancer cells to produce bioactive-TGFβ and to create an immunosuppressive micro-environment.