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

Abstract

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-ALK5flox/flox (ALK5ΔCD8) mice reject tumors in high proportions, dependent on CD8+ T cells. ALK5ΔCD8 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 ALK5ΔCD8 host. These data demonstrate a mechanism of TGFβ immunosuppression through inhibition of CXCR3 in CD8+ T cells, thereby limiting their trafficking into tumors.

CXCL9-expressing tumor-associated macrophages: new players in the fight against cancer

“…[53][54][55] Alternatively, exploiting opportunities to increase the stability of the CXCR3-CXCL9/10 axis may prove promising, for instance, enhancing CXCL10 protein stability by DPP4 inhibition, 29 or preventing the downregulation of CD8 T cell CXCR3 expression by tumor-derived TGFβ. 56 Finally, depletion of mature macrophages may allow for enhanced infiltration of inflammatory monocytes with the potential to differentiate into CXCL9-expressing TAMs, such as has recently been shown using Lif, CD163, Trem2 or Tyro-Axl-Mer receptor antagonists. [57][58][59][60] In this context, there should be…”

Therapeutic targeting of TGF-β in cancer: hacking a master switch of immune suppression

“…Tgf-β is constitutively expressed in the thymus and forms an essential factor during negative selection as it leads to increased expression of pro-apoptotic Bcl2-like protein Bim, specifically in autoreactive T cells, resulting in apoptosis via caspase-3 [48]. In addition, up-regulation of chemokine receptor Cxcr3, in the absence of Tgf-β, results in aberrant localization of T cells in the thymus and escape from negative selection as they avoid interaction with medullary thymic epithelial cells [48,49]. Furthermore, the maturation of medullary thymic epithelial cells is also impaired in the absence of Tgf-β which further supports the accumulation of autoreactive T cells [48].…”

EZH2 as a Regulator of CD8+ T Cell Fate and Function

“…Thus, EZH2 is a relevant target in cancer therapies attempting to improve T cell recruitment into the TME. Specifically, expression of CXCR3 on T cells, which binds to ligands CXCL9/CXCL10, was highlighted in recent findings to be critical for drawing T cells into the TME and informs the design of future therapeutics with a primary aim of improving T cell recruitment (49,(52)(53)(54). Furthermore, the effect of EZH2 inhibition on destabilizing the regulatory T cell lineage is another primary consideration that was demonstrated to impact antitumor immunity (48,55).…”