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 by 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 cross-talk between myeloid cells and T cells 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.

• Authors: Chanyu Yue, Shudan Shen, Jiehui Deng, Saul J Priceman, Wenzhao Li, Austin Huang, Hua Yu
• Journal: Cancer immunology research (Cancer Immunol Res) Vol. 3 Issue 8 Pg. 864-870 (Aug 2015) ISSN: 2326-6074 [Electronic] United States
• PMID: 26025380 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• Chemokine CXCL10
• Chemokines
• Receptors, CXCR3
• STAT3 Transcription Factor
• Interferon-gamma

Topics

• Animals
• CD8-Positive T-Lymphocytes (immunology, metabolism, pathology)
• Cell Movement (immunology)
• Chemokine CXCL10 (metabolism)
• Chemokines (metabolism)
• Disease Models, Animal
• Down-Regulation
• Gene Knockout Techniques
• Humans
• Interferon-gamma (metabolism)
• Lymphocytes, Tumor-Infiltrating (immunology, metabolism)
• Melanoma, Experimental
• Mice
• Mice, Transgenic
• Myeloid Cells (immunology, metabolism)
• Neoplasms (genetics, immunology, metabolism, pathology)
• Receptors, CXCR3 (metabolism)
• STAT3 Transcription Factor (genetics, metabolism)
• Signal Transduction