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TGFβ suppresses CD8+ T cell expression of CXCR3 and tumor trafficking
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Journal Article
TGFβ suppresses CD8+ T cell expression of CXCR3 and tumor trafficking
2020
Overview
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
flox/flox
(ALK5
ΔCD8
) mice reject tumors in high proportions, dependent on CD8
+
T cells. ALK5
ΔCD8
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. TGFβ reduces CXCR3 expression, and increases binding of Smad2 to the CXCR3 promoter. In vivo CXCR3 blockade partially abrogates the survival advantage of an ALK5
ΔCD8
host. These data demonstrate a mechanism of TGFβ immunosuppression through inhibition of CXCR3 in CD8
+
T cells, thereby limiting their trafficking into tumors.
TGFβ has a role in cancer immunosuppression but the exact mechanisms haven’t been fully elucidated. Here, using mouse models deficient in TGFβ-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.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/31
/ 13/51
/ 38/15
/ 38/77
/ 64/60
/ 96/106
/ Animals
/ Cancer
/ CD8-Positive T-Lymphocytes - drug effects
/ CD8-Positive T-Lymphocytes - metabolism
/ Cell Movement - drug effects
/ Cell Survival - drug effects
/ Chemokine CXCL10 - metabolism
/ Flox
/ Gene Expression Regulation - drug effects
/ Humanities and Social Sciences
/ Promoter Regions, Genetic - genetics
/ Protein Binding - drug effects
/ Receptors, CXCR3 - metabolism
/ Science
/ Toxicity
/ Transforming Growth Factor beta - pharmacology
/ Transforming growth factor-b
/ Tumors
