Integrin ?v?8-expressing tumor cells evade host immunity by regulating TGF-? activation in immune cells.

ABSTRACT: TGF-? 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-? (L-TGF-?) is activated in the tumor microenvironment could facilitate cell- and mechanism-specific approaches to immunotherapeutically target TGF-?. Binding of L-TGF-? to integrin ?v?8 results in activation of TGF-?. We engineered and used ?v?8 antibodies optimized for blocking or detection, which - respectively - inhibit tumor growth in syngeneic tumor models or sensitively and specifically detect ?8 in human tumors. Inhibition of ?v?8 potentiates cytotoxic T cell responses and recruitment of immune cells to tumor centers - effects that are independent of PD-1/PD-L1. ?8 is expressed on the cell surface at high levels by tumor cells, not immune cells, while the reverse is true of L-TGF-?, suggesting that tumor cell ?v?8 serves as a platform for activating cell-surface L-TGF-? presented by immune cells. Transcriptome analysis of tumor-associated lymphoid cells reveals macrophages as a key cell type responsive to ?8 inhibition with major increases in chemokine and tumor-eliminating genes. High ?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 ?v?8 is a PD-1/PD-L1-independent immunotherapeutic target.

SUBMITTER: Takasaka N 

PROVIDER: S-EPMC6237456 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature