BioProject

Galectin-9 (Gal-9) is a versatile immuno-modulatory protein. Its contribution to the expansion of suppressive myeloid cells in human tumors remain to be investigated. More...

Galectin-9 (Gal-9) is a versatile immuno-modulatory protein. Its contribution to the expansion of suppressive myeloid cells in human tumors remain to be investigated. For this aim, we used in vitro models bringing together carcinoma cells derived from nasopharyngeal carcinomas (NPC) and CD33+ myeloid precursors. We found that Gal-9 expression in carcinoma cells enhances the generation of HLA-DR-CD33+CD11b+ myeloid-derived suppressor cells (MDSCs) in bystander cells. The underlying mechanisms involve both the intra-cellular 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 and recruitment, including IL-1b, IL-6, CCL22, and CX3CL1. This effect is mediated by accelerated degradation of the STING protein resulting from direct interaction of the Gal-9 carbohydrate recognition domain 1 with the STING C-terminus and subsequent enhancement of the TRIMP29-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, clinical data from NPC patients show that high concentrations of Gal-9 in tumor cells and plasma samples are associated with shortened disease-free survival. These findings unearth a novel contribution of Gal-9 to the generation of an immunosuppressive microenvironment which favors tumor development. Overall design: Examination of 2 different human nasopharyngeal carcinomas cells. Less...