Integrin αvβ8-expressing tumor cells evade host immunity by regulating TGF-β activation in immune cells.

TGF-beta is a promising immunotherapeutic target. It is expressed ubiquitously in a latent form that must be activated to function. Determination of where and how latent TGF-beta (L-TGF-beta) is activated in the tumor microenvironment could facilitate cell- and mechanism-specific approaches to immunotherapeutically target TGF-beta. Binding of L-TGF-beta to integrin alpha v beta 8 results in activation of TGF-beta. We engineered and used alpha v beta 8 antibodies optimized for blocking or detection, which - respectively inhibit tumor growth in syngeneic tumor models or sensitively and specifically detect beta 8 in human tumors. Inhibition of alpha v beta 8 potentiates cytotoxic T cell responses and recruitment of immune cells to tumor centers - effects that are independent of PD-1/PD-L1. beta 8 is expressed on the cell surface at high levels by tumor cells, not immune cells, while the reverse is true of L-TGF-beta, suggesting that tumor cell alpha v beta 8 serves as a platform for activating cell-surface L-TGF-beta presented by immune cells. Transcriptome analysis of tumor-associated lymphoid cells reveals macrophages as a key cell type responsive to beta 8 inhibition with major increases in chemokine and tumor-eliminating genes. High beta 8 expression in tumor cells is seen in 20%-80% of various cancers, which rarely coincides with high PD-L1 expression. These data suggest tumor cell alpha v beta 8 is a PD-1/PD-L1-independent immunotherapeutic target.