Galectin-9 promotes a suppressive microenvironment in human cancer by enhancing STING degradation
Galectin-9 promotes a suppressive microenvironment in human cancer by enhancing STING degradation
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Galectin-9 通过增强 STING 降解促进人类癌症的抑制性微环境
DOI：
10.1038/s41389-020-00248-0
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发表时间：
2020-07-06
期刊：
影响因子：
6.2
通讯作者：
Li, Jiang
中科院分区：
文献类型：
--
作者：
Zhang, Chuan-xia;Huang, Dai-jia;Li, Jiang
已知Galectin-9(Gal-9)可促进小鼠模型中髓系抑制细胞(MDSCs)的增殖。它对MDSCs在人类恶性肿瘤中扩增的作用仍有待研究。我们报道了Gal-9在鼻咽癌细胞中的表达促进了CD33+CD11b+HLADR−从旁观者细胞产生MDSC。其潜在的机制涉及细胞内和分泌的Gal-9。在癌细胞内部，GAL-9上调多种对骨髓间充质干细胞分化至关重要的促炎细胞因子的表达，包括IL-1β和IL-6。这种作用是通过Gal-9碳水化合物识别结构域1与STINC末端直接相互作用以及随后增强E3泛素连接酶TRIM29介导的K48连接的STING泛素化而加速的STIN蛋白降解。此外，我们还发现癌细胞分泌的胞外Gal-9可以进入髓系细胞，并触发相同的信号级联反应。一直以来，高浓度的肿瘤和血浆Gal-9与鼻咽癌患者的生存期缩短有关。我们的发现发现，Gal-9通过抑制刺痛信号在肿瘤微环境中诱导髓系介导的免疫抑制。
Galectin-9 (Gal-9) is known to enhance the expansion of myeloid-derived suppressor cells (MDSCs) in murine models. Its contribution to the expansion of MDSCs in human malignancies remain to be investigated. We here report that Gal-9 expression in nasopharyngeal carcinoma (NPC) cells enhances the generation of MDSCs (CD33+CD11b+HLA-DR−) from CD33+bystander cells. The underlying mechanisms involve both the intracellular and secreted Gal-9. Inside carcinoma cells, Gal-9 up-regulates the expression of a variety of pro-inflammatory cytokines which are critical for MDSC differentiation, including IL-1β and IL-6. This effect is mediated by accelerated STING protein degradation resulting from direct interaction of the Gal-9 carbohydrate recognition domain 1 with the STING C-terminus and subsequent enhancement of the E3 ubiquitin ligase TRIM29-mediated K48-linked ubiquitination of STING. Moreover, we showed that extracellular Gal-9 secreted by carcinoma cells can enter the myeloid cells and trigger the same signaling cascade. Consistently, high concentrations of tumor and plasma Gal-9 are associated with shortened survival of NPC patients. Our findings unearth that Gal-9 induces myeloid lineage-mediated immunosuppression in tumor microenvironments by suppressing STING signaling.