CXCL4 is mainly produced by activated platelets, but 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. Here 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.
Dr. Wei Han completed his Ph.D. in Molecular Biology from Mount Sinai School of Medicine at NYC in 1994 followed by a postdoctoral training at Memorial Sloan-Kettering Cancer Center. He is now a professor at Shanghai Jiao Tong University and Founder of General Regeneratives (Shanghai) Ltd. He developed a proprietary “Prometheus Technology” to discover genes important for multiple tissue regeneration and repair, including bone marrow, liver, pancreas, cartilage, gut epithelial, and thymus. Over the years, a series of investigational new drugs were developed. The most advanced candidate with global patents, GR007, a multi-organ protector against chemotoxicities has demonstrated its good safety profile and preliminary efficacy in phase 1 clinical trial, and phase 2 clinical trial is ongoing.