title: 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.affiliation: Department of Cancer Immunotherapeutics and Tumor Immunology, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA.
authors.forename: Chanyu
authors.initials: C
authors.lastname: Yue
authors.affiliation: Department of Cancer Immunotherapeutics and Tumor Immunology, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA.
authors.forename: Shudan
authors.initials: S
authors.lastname: Shen
authors.affiliation: Department of Cancer Immunotherapeutics and Tumor Immunology, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA.
authors.forename: Jiehui
authors.initials: J
authors.lastname: Deng
authors.affiliation: Department of Cancer Immunotherapeutics and Tumor Immunology, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA.
authors.forename: Saul J
authors.initials: SJ
authors.lastname: Priceman
authors.affiliation: Department of Cancer Immunotherapeutics and Tumor Immunology, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA.
authors.forename: Wenzhao
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Cancer Immunotherapeutics and Tumor Immunology, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA.
authors.forename: Austin
authors.initials: A
authors.lastname: Huang
authors.affiliation: Department of Cancer Immunotherapeutics and Tumor Immunology, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Yu
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D002465:Cell Movement / Q000276:immunology; D054357:Chemokine CXCL10 / Q000378:metabolism*; D018925:Chemokines / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation; D055786:Gene Knockout Techniques; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism; D008546:Melanoma, Experimental; D051379:Mice; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D054367:Receptors, CXCR3 / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D054357:Chemokine CXCL10; D018925:Chemokines; D054367:Receptors, CXCR3; D050796:STAT3 Transcription Factor; D007371:Interferon-gamma