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- Title
Galectin-9 promotes a suppressive microenvironment in human cancer by enhancing STING degradation.
- Authors
Zhang, Chuan-xia; Huang, Dai-jia; Baloche, Valentin; Zhang, Lin; Xu, Jing-xiao; Li, Bo-wen; Zhao, Xin-rui; He, Jia; Mai, Hai-qiang; Chen, Qiu-yan; Zhang, Xiao-shi; Busson, Pierre; Cui, Jun; Li, Jiang
- Abstract
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.
- Publication
Oncogenesis, 2020, Vol 9, Issue 7, p1
- ISSN
2157-9024
- Publication type
Article
- DOI
10.1038/s41389-020-00248-0