STAT3 in CD8+ T Cells Inhibits Their Tumor Accumulation by Downregulating CXCR3/CXCL10 Axis

Abstract

One of the obstacles for cancer immunotherapy is the inefficiency of CD8+ T-cell recruitment to tumors. STAT3 has been shown to suppress CD8+ T-cell antitumor functions in various cancer models, in part by restricting accumulation of CD8+ T cells. However, the underlying molecular mechanism by which STAT3 in CD8+ T cells inhibits their accumulation in tumors remains to be defined. Here, we show that STAT3 signaling in CD8+ T cells inhibits chemokine CXCL10 production by tumor-associated myeloid cells via reducing IFNγ expression by T cells. We further demonstrate that ablating STAT3 in T cells allows expression of CXCR3, the receptor of CXCL10, on CD8+ T cells, resulting in efficient accumulation of CD8+ T cells at tumor sites. Blocking IFNγ or CXCR3 impairs the accumulation of STAT3-deficient CD8+ T cells in tumor and their antitumor effects. Together, our study reveals a negative regulation by STAT3 signaling in T cells on myeloid cell-T cell crosstalk through IFNγ/CXCR3/CXCL10, which is important for CD8+ T cells homing to tumors. Our results thus provide new insights applicable to cancer immunotherapy and adoptive T-cell strategies.

Failed immune responses across multiple pathologies share pan-tumor and circulating lymphocytic targets

“…We observed increased MMP9 expression in both CD8 + and CD19 + ccRCC ptPBLs, and other genes we find correlating with MMP9 expression are implicated in CD8 + cross-priming and antigen-mediated activation and proliferation (CD69, STAT4, NFIL3, IL10, and JAK1) (40,59,60). In patients with recurring pan-cancers, MMP9 was inversely correlated with its regulator STAT3, which restricts tumor penetration of anti-tumor CD8 + T cells (61,62). In pooled RNA PCA analyses, MMP9 expression correlated with TILs and CXCL13, which induces MMP-9 expression toward leukocyte migration in perivascular spaces (63,64).…”

A STAT3-dependent transcriptional circuitry inhibits cytotoxic gene expression in T cells

“…Indeed, Stat3 disruption promotes responses against experimental tumors (65). Even though the exact mechanisms by which STAT3 inhibits antitumoral activity remain to be elucidated, a growing number of reports suggest a critical role of STAT3 and IL-6 signaling in T cells and natural killer cells, consistent with an effect on cytotoxic gene expression (66)(67)(68)(69). Thus, the ability to manipulate and target this pathway might be a valuable approach to enhance antitumor responses in cancer immunotherapy strategies.…”

Nifuroxazide prompts antitumor immune response of TCL-loaded DC in mice with orthotopically-implanted hepatocarcinoma

“…However, in the body of tumor patients exist a large number of immature DC that could not provide the costimulation signals to help T cell development and proliferation (22). Activation of STAT3 has been proved to inhibit the function of immune cells including DCs, NK cells, macrophages and T cells (23)(24)(25)(26). Furthermore, the activation of STAT3 also played a key role in the progress of HCC (27,28).…”

“…However, TCL-loaded DC might play a dual role by inducing low antitumor tumor responses and attenuating T cell immune responses (31). In addition, the activation of STAT3 has been demonstrated not only to suppress the DC maturity, but also to inhibit the proliferation of T lymphocytes, the infiltration of NK cells and the antitumor immune response (23)(24)(25)(26). In our experiments, treatment with nifuroxazide or TCL-loaded DC increased the T lymphocyte infiltration in tumor tissues and the ratio of CD8 + T and NK cells in the spleen.…”