Non-platelet-derived CXCL4 differentially regulates cytotoxic and regulatory T cells through CXCR3 to suppress the immune response to colon cancer
Non-platelet-derived CXCL4 differentially regulates cytotoxic and regulatory T cells through CXCR3 to suppress the immune response to colon cancer
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非血小板衍生的 CXCL4 通过 CXCR3 差异调节细胞毒性和调节性 T 细胞，以抑制对结肠癌的免疫反应
DOI：
10.1016/j.canlet.2018.11.017
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发表时间：
2019-01-01
期刊：
影响因子：
9.7
通讯作者：
Han, Wei
中科院分区：
文献类型：
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作者：
Deng, Shaorong;Deng, Qing;Han, Wei
CXCL4主要由活化的血小板产生，某些体细胞和癌细胞也表达CXCL4。然而，非血小板来源的CXCL4的生理功能尚不清楚。此前，我们报道了癌细胞产生的CXCL4通过抑制细胞毒性T淋巴细胞（CTL）的抗肿瘤活性来加速肿瘤生长。为了阐明CXCL4在肿瘤免疫中的机制，我们通过肌内电分离比较了过表达CXCL4的CXCL4(-/-)、CXCR3(-/-)和C57BL/6小鼠的CTL和调节性T细胞(Treg)。 CXCL4 加速 CXCL4 和 C57BL/6 小鼠的肿瘤生长，但不加速 CXCR3(-/-) 小鼠的肿瘤生长。此外，CXCL4 降低 CPI 增殖和 IFN-γ 产生，增强 CTL 凋亡和程序性死亡 1 (PD-1) 表达。相反，CXCL4 促进 Tregs 增殖和 TGF-β 产生，并下调 Tregs 中的 PD-1 表达。值得注意的是，CXCL4 的这些作用在野生型小鼠的脾脏和肿瘤浸润 CTL 和 Tregs 中均观察到，但在 CXCR3(-/-) 小鼠中未观察到。因此，我们揭示了非血小板衍生的CXCL4通过CXCR3的负性免疫调节功能，癌细胞可以劫持该功能来逃避宿主免疫系统，这表明CXCL4/CXCR3轴可能作为结直肠癌免疫治疗的新靶点。
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.