title: CD8+ T-cell immunosurveillance constrains lymphoid premetastatic myeloid cell accumulation.
abstract: Increasing evidence suggests that premetastatic niches, consisting mainly of myeloid cells, provide microenvironment critical for cancer cell recruitment and survival to facilitate metastasis. While CD8(+) T cells exert immunosurveillance in primary human tumors, whether they can exert similar effects on myeloid cells in the premetastatic environment is unknown. Here, we show that CD8(+) T cells are capable of constraining premetastatic myeloid cell accumulation by inducing myeloid cell apoptosis in C57BL/6 mice. Ag-specific CD8(+) T-cell cytotoxicity against myeloid cells in premetastatic lymph nodes is compromised by Stat3. We demonstrate here that Stat3 ablation in myeloid cells leads to CD8(+) T-cell activation and increased levels of IFN-γ and granzyme B in the premetastatic environment. Furthermore, Stat3 negatively regulates soluble Ag cross-presentation by myeloid cells to CD8(+) T cells in the premetastatic niche. Importantly, in tumor-free lymph nodes of melanoma patients, infiltration of activated CD8(+) T cells inversely correlates with STAT3 activity, which is associated with a decrease in number of myeloid cells. Our study suggested a novel role for CD8(+) T cells in constraining myeloid cell activity through direct killing in the premetastatic environment, and the therapeutic potential by targeting Stat3 in myeloid cells to improve CD8(+) T-cell immunosurveillance against metastasis.
authors.affiliation: Department of Cancer Immunotherapeutics and Tumor Immunology, Beckman Research Institute and City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
authors.forename: Wang
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Cancer Immunotherapeutics and Tumor Immunology, Beckman Research Institute and City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Cancer Immunotherapeutics and Tumor Immunology, Beckman Research Institute and City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
authors.forename: Wenzhao
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Cancer Immunotherapeutics and Tumor Immunology, Beckman Research Institute and City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
authors.forename: Jiehui
authors.initials: J
authors.lastname: Deng
authors.affiliation: Department of Cancer Immunotherapeutics and Tumor Immunology, Beckman Research Institute and City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
authors.forename: Andreas
authors.initials: A
authors.lastname: Herrmann
authors.affiliation: Department of Cancer Immunotherapeutics and Tumor Immunology, Beckman Research Institute and City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
authors.forename: Saul J
authors.initials: SJ
authors.lastname: Priceman
authors.affiliation: Department of Molecular Medicine, Beckman Research Institute and City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Liang
authors.affiliation: Department of Cancer Immunotherapeutics and Tumor Immunology, Beckman Research Institute and City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
authors.forename: Shudan
authors.initials: S
authors.lastname: Shen
authors.affiliation: Department of Medical Oncology, Beckman Research Institute and City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
authors.forename: Sumanta K
authors.initials: SK
authors.lastname: Pal
authors.affiliation: Department of Molecular Oncology, John Wayne Cancer Institute, Santa Monica, CA 90404, USA.
authors.forename: Dave S B
authors.initials: DSB
authors.lastname: Hoon
authors.affiliation: Department of Cancer Immunotherapeutics and Tumor Immunology, Beckman Research Institute and City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Yu
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology*; D053804:Granzymes / Q000235:genetics / Q000276:immunology; D006801:Humans; D007157:Immunologic Surveillance; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D008207:Lymphatic Metastasis; D017737:Macrophages, Peritoneal / Q000276:immunology* / Q000473:pathology; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D061251:Primary Cell Culture; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000473:pathology
chemical_list: D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D007371:Interferon-gamma; D053804:Granzymes; C509214:Gzmb protein, mouse
keywords: CTLs; Immunosurveillance; Premetastatic myeloid cell accumulation; Stat3