A Tumor-Specific Mechanism Of T-Reg Enrichment Mediated By The Integrin Alpha V Beta 8

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 alpha v beta 8 integrin. Tumor cell alpha v beta 8 bound to latent transforming growth factor-beta (L-TGF-beta) presented on the surface of T cells, resulting in TGF-beta activation and immunosuppressive T-reg differentiation in vitro. In vivo, tumor cell alpha v beta 8 expression correlated with T-reg enrichment, immunosuppressive T-reg gene expression, and increased tumor growth, which was reduced in mice by alpha v beta 8 inhibition or T-reg depletion. Structural modeling and cell-based studies suggested a highly geometrically constrained complex forming between alpha v beta 8-expressing tumor cells and L-TGF-beta-expressing T cells, facilitating TGF-beta activation, independent of release and diffusion, and providing limited access to TGF-beta inhibitors. These findings suggest a highly localized tumor-specific mechanism for T-reg enrichment.