Non-platelet-derived CXCL4 differentially regulates cytotoxic and regulatory T cells through CXCR3 to suppress the immune response to colon cancer

• Published in: Cancer letters Vol. 443; pp. 1 - 12
• Main Authors: Deng, Shaorong, Deng, Qing, Zhang, Yingjie, Ye, Hao, Yu, Xiaolan, Zhang, Yang, Han, Grace YQ, Luo, Ping, Wu, Mingyuan, Yu, Yan, Han, Wei
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 28-02-2019; Elsevier Limited
• Subjects: Apoptosis; Blood platelets; Cancer immunology; Cancer immunotherapy; Colon cancer; Colorectal cancer; Colorectal carcinoma; CXCL4; CXCR3; CXCR3 protein; Cytokines; Cytotoxicity; Electroporation; Flow cytometry; Immune response; Immunoglobulins; Immunology; Immunoregulation; Immunotherapy; Lymphocytes; Lymphocytes T; Mice; Musculoskeletal system; PD-1 protein; Plasmids; Platelets; Psoriasis; Regulation; Roles; Somatic cells; Spleen; γ-Interferon; Oregon; United States > US; China; Cancer immunology; Cancer immunotherapy; CXCR3; Colorectal cancer; CXCL4
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2018.11.017

CXCL4 is mainly produced by activated platelets, and certain somatic cells and cancer cells also express CXCL4. However, the physiological function of non-platelet-derived CXCL4 is unclear. Previously, we reported that CXCL4 produced by cancer cells accelerated tumor growth by suppressing the antitumor activities of cytotoxic T lymphocytes (CTLs). To elucidate the mechanism of CXCL4 in tumor immunity, we compared the CTLs and regulatory T cells (Tregs) from CXCL4−/−, CXCR3−/− and C57BL/6 mice overexpressing CXCL4 via intramuscular electroporation. CXCL4 accelerated tumor growth in CXCL4−/− and C57BL/6 mice but not in CXCR3−/− mice. Furthermore, CXCL4 decreased CTLs proliferation and IFN-γ production and enhanced CTLs apoptosis and programmed death 1 (PD-1) expression. Conversely, CXCL4 promoted Tregs proliferation and TGF-β production and downregulated PD-1 expression in Tregs. Notably, these effects of CXCL4 were both observed in the splenic and tumor-infiltrating CTLs and Tregs from wild-type but not CXCR3−/− mice. Thus, we revealed a negative immune regulatory function for non-platelet-derived CXCL4 through CXCR3 that cancer cells could hijack to evade the host immune system, suggesting that the CXCL4/CXCR3 axis may serve as a novel target for colorectal cancer immunotherapy.
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•Non-platelet-derived CXCL4 accelerates growth of mouse colon cancer in vivo.•The CXCL4 suppresses antitumor immune response to colon cancer via receptor CXCR3.•The CXCL4 suppresses the function of cytotoxic T lymphocytes in colon cancer mice.•The CXCL4 enhances the function of regulatory T cells in colon cancer mice.