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

作者：Deng, Shaorong; Deng, Qing; Zhang, Yingjie; Ye, Hao; Yu, Xiaolan; Zhang, Yang; Han, Grace Y. Q.; Luo, Ping; Wu, Mingyuan; Yu, Yan^*; Han, Wei^*

来源：Cancer Letters, 2019, 443: 1-12.

DOI：10.1016/j.canlet.2018.11.017

• CXCL4
• CXCR3
• Colorectal cancer
• Cancer immunology
• Cancer immunotherapy

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 electroparation. CXCL4 accelerated tumor growth in CXCL4 and C57BL/6 mice but not in CXCR3(-/-) mice. Furthermore, CXCL4 decreased CPIs proliferation and IFN-gamma production and enhanced CTLs apoptosis and programmed death 1 (PD-1) expression. Conversely, CXCL4 promoted Tregs proliferation and TGF-beta 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.

• 出版日期2019
• 单位上海交通大学