α2,6-Sialoglycan-regulated antitumor immunity of tumor-infiltrating CD8⁺ T cells

Cell-surface sialoglycans overexpressed on cancer cells suppress activation of tumor-infiltrating immune cells (TIICs) and thus represent promising targets for cancer immunotherapy. However, the functional roles of sialylation in TIICs remain incompletely understood. Here we developed a strategy for single-cell correlative analysis of α2,3- and α2,6-linked sialoglycans and transcriptomes to determine the correlations of cell-surface sialylation with gene expression of the same cells in a linkage-specific manner by single-cell RNA sequencing. We found that α2,3- and α2,6-sialoglycans were distinctively regulated across specific TIIC subpopulations in murine tumors. Notably, downregulation of α2,6-sialoglycans was identified as a cell-surface marker for intratumoral tumor-specific antigen-reactive CD8⁺ T cells with high avidity. Mechanistically, high-avidity (but not low-avidity) activation of murine CD8⁺ T cells within the tumor suppressed β-galactoside α2,6-sialyltransferase 1 expression, which downregulates α2,6-sialylation and exposes galectin-1 ligands. Functionally, galectin-1 binding promoted T cell apoptosis and immune evasion in cancer. This work demonstrates the functional significance and therapeutic potential of specific sialoglycans on TIICs.