Abstract
TGF-β 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-β (L-TGF-β) is activated in the tumor microenvironment could facilitate cell- and mechanism-specific approaches to immunotherapeutically target TGF-β. Binding of L-TGF-β to integrin αvβ8 results in activation of TGF-β. We engineered and used αvβ8 antibodies optimized for blocking or detection, which — respectively — inhibit tumor growth in syngeneic tumor models or sensitively and specifically detect β8 in human tumors. Inhibition of αvβ8 potentiates cytotoxic T cell responses and recruitment of immune cells to tumor centers — effects that are independent of PD-1/PD-L1. β8 is expressed on the cell surface at high levels by tumor cells, not immune cells, while the reverse is true of L-TGF-β, suggesting that tumor cell αvβ8 serves as a platform for activating cell-surface L-TGF-β presented by immune cells. Transcriptome analysis of tumor-associated lymphoid cells reveals macrophages as a key cell type responsive to β8 inhibition with major increases in chemokine and tumor-eliminating genes. High β8 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 αvβ8 is a PD-1/PD-L1–independent immunotherapeutic target.
Authors
Naoki Takasaka, Robert I. Seed, Anthony Cormier, Andrew J. Bondesson, Jianlong Lou, Ahmed Elattma, Saburo Ito, Haruhiko Yanagisawa, Mitsuo Hashimoto, Royce Ma, Michelle D. Levine, Jean Publicover, Rashaun Potts, Jillian M. Jespersen, Melody G. Campbell, Fraser Conrad, James D. Marks, Yifan Cheng, Jody L. Baron, Stephen L. Nishimura
Figure 4
The antibody C6D4 decreases CD4+ Tregs, increases CD8+ and NK1.1+ IFN-γ–secreting cells, and alters differentiation of TAM.
