Non-platelet-derived CXCL4 differentially regulates cytotoxic and regulatory T cells through CXCR3 to suppress the immune response to colon cancer
2019
Abstract 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
CTLsand regulatory T cells (Tregs) from CXCL4 −/− ,
CXCR3−/− and
C57BL/6mice overexpressing CXCL4 via intramuscular
electroporation. CXCL4 accelerated tumor growth in CXCL4 −/− and
C57BL/6mice but not in
CXCR3−/− mice. Furthermore, CXCL4 decreased
CTLsproliferation and IFN-γ production and enhanced
CTLsapoptosis 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
CTLsand Tregs from wild-type but not
CXCR3−/− mice. Thus, we revealed a negative immune regulatory function for non-platelet-derived CXCL4 through
CXCR3that cancer cells could hijack to evade the host immune system, suggesting that the CXCL4/
CXCR3axis may serve as a novel target for colorectal
cancer immunotherapy.
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