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TGF? suppresses CD8+ T cell expression of CXCR3 and tumor trafficking.

ABSTRACT: Transforming growth factor beta (TGF?) is a multipotent immunosuppressive cytokine. TGF? excludes immune cells from tumors, and TGF? inhibition improves the efficacy of cytotoxic and immune therapies. Using preclinical colorectal cancer models in cell type-conditional TGF? 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?Cre-ALK5flox/flox (ALK5?CD8) mice reject tumors in high proportions, dependent on CD8+ T cells. ALK5?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? reduces CXCR3 expression, and increases binding of Smad2 to the CXCR3 promoter. In vivo CXCR3 blockade partially abrogates the survival advantage of an ALK5?CD8 host. These data demonstrate a mechanism of TGF? immunosuppression through inhibition of CXCR3 in CD8+ T cells, thereby limiting their trafficking into tumors.

SUBMITTER: Gunderson AJ 

PROVIDER: S-EPMC7145847 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Transforming growth factor beta (TGFβ) is a multipotent immunosuppressive cytokine. TGFβ excludes immune cells from tumors, and TGFβ inhibition improves the efficacy of cytotoxic and immune therapies. Using preclinical colorectal cancer models in cell type-conditional TGFβ 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, CD8αCre-ALK5<sup>flox/flox</sup> (ALK5  ...[more]

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