A tumor-specific mechanism of T_reg enrichment mediated by the integrin αvβ8

Regulatory T cells (T_regs) that promote tumor immune evasion are enriched in certain tumors and correlate with poor prognosis. However, mechanisms for T_reg enrichment remain incompletely understood. We described a mechanism for T_reg enrichment in mouse and human tumors mediated by the αvβ8 integrin. Tumor cell αvβ8 bound to latent transforming growth factor-β (L-TGF-β) presented on the surface of T cells, resulting in TGF-β activation and immunosuppressive T_reg differentiation in vitro. In vivo, tumor cell αvβ8 expression correlated with T_reg enrichment, immunosuppressive T_reg gene expression, and increased tumor growth, which was reduced in mice by αvβ8 inhibition or T_reg depletion. Structural modeling and cell-based studies suggested a highly geometrically constrained complex forming between αvβ8-expressing tumor cells and L-TGF-β-expressing T cells, facilitating TGF-β activation, independent of release and diffusion, and providing limited access to TGF-β inhibitors. These findings suggest a highly localized tumor-specific mechanism for T_reg enrichment.