Takasaka et al. demonstrated that integrin αvβ8 is expressed on tumor cells, while the latent form of TGF-β, which is activated by αvβ8, is expressed on T cells and macrophages within the tumor. Antibody blockade of αvβ8 reduced tumor growth and improved survival in mice by increasing tumor apoptosis and infiltration of proinflammatory TAMs as well as IFNγ-producing CD8+ T cells and NK cells, while decreasing Tregs and angiogenesis. These effects were independent of the PD-1/PD-L1 pathway. In human epithelial cancers, high β8 expression rarely coincided with high PD-L1 expression and was associated with decreased survival.
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 alphavbeta8 results in activation of TGF-beta. We engineered and used alphavbeta8 antibodies optimized for blocking or detection, which - respectively - inhibit tumor growth in syngeneic tumor models or sensitively and specifically detect beta8 in human tumors. Inhibition of alphavbeta8 potentiates cytotoxic T cell responses and recruitment of immune cells to tumor centers - effects that are independent of PD-1/PD-L1. beta8 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 alphavbeta8 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 beta8 inhibition with major increases in chemokine and tumor-eliminating genes. High beta8 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 alphavbeta8 is a PD-1/PD-L1-independent immunotherapeutic target.