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.

已知 Galectin-9 (Gal-9) 可增强小鼠模型中髓源性抑制细胞 (MDSC) 的扩增。它对人类恶性肿瘤中 MDSCs 扩展的贡献仍有待研究。我们在此报告鼻咽癌 (NPC) 细胞中的 Gal-9 表达增强了从 CD33 ^{+生成 MDSC (CD33 +} CD11b ⁺ HLA-DR ^- )旁观者细胞。潜在的机制涉及细胞内和分泌的 Gal-9。在癌细胞内部，Gal-9 上调多种促炎细胞因子的表达，这些细胞因子对 MDSC 分化至关重要，包括 IL-1β 和 IL-6。这种效应是由 Gal-9 碳水化合物识别结构域 1 与 STING C 末端的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 泛素化导致的加速 STING 蛋白降解介导的。此外，我们发现癌细胞分泌的细胞外 Gal-9 可以进入骨髓细胞并触发相同的信号级联。一致地，高浓度的肿瘤和血浆 Gal-9 与 NPC 患者的生存期缩短有关。