Regulatory T cells promote cancer immune-escape through integrin alpha v beta 8-mediated TGF-beta activation

Presence of TGF beta in the tumor microenvironment is one of the most relevant cancer immune-escape mechanisms. TGF beta 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 beta 8 chain of alpha v beta 8 integrin (Itg beta 8) are the main cell type in the tumors that activates TGF beta, produced by the cancer cells and stored in the tumor micro-environment. Itg beta 8 ablation in Treg cells impairs TGF beta 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-Itg beta 8 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-TGF beta and to create an immunosuppressive micro-environment. TGF beta is secreted in an inactive form in the tumor microenvironment. Authors here show that although TGF beta is produced mainly by cancer cells, regulatory T cells are necessary for its activation via expression of the b8 chain of avb8 integrin. Thus, both cell types contribute to TGF beta dependent tumor growth.