TGFβ suppresses CD8+ T cell expression of CXCR3 and tumor trafficking

Transforming growth factor beta (TGF beta) is a multipotent immunosuppressive cytokine. TGF beta excludes immune cells from tumors, and TGF beta inhibition improves the efficacy of cytotoxic and immune therapies. Using preclinical colorectal cancer models in cell type-conditional TGF beta receptor I (ALK5) knockout mice, we interrogate this mechanism. Tumor growth delay and radiation response are unchanged in animals with Treg or macrophage-specific ALK5 deletion. However, CD8 alpha Cre-ALK5(flox/flox) (ALK5(Delta CD8)) mice reject tumors in high proportions, dependent on CD8(+) T cells. ALK5(Delta CD8) mice have more tumor-infiltrating effector CD8(+) T cells, with more cytotoxic capacity. ALK5-deficient CD8(+) T cells exhibit increased CXCR3 expression and enhanced migration towards CXCL10. TGF beta reduces CXCR3 expression, and increases binding of Smad2 to the CXCR3 promoter. In vivo CXCR3 blockade partially abrogates the survival advantage of an ALK5(Delta CD8) host. These data demonstrate a mechanism of TGF beta immunosuppression through inhibition of CXCR3 in CD8(+) T cells, thereby limiting their trafficking into tumors. TGF beta has a role in cancer immunosuppression but the exact mechanisms haven't been fully elucidated. Here, using mouse models deficient in TGF beta -signaling, the authors show that loss of ALK5 in CD8+T cells enhances their tumour trafficking and cytotoxicity suggesting that ALK5 inhibitors may have clinical utility.