The lectin Siglec-G functions as an inhibitory receptor in CD8+ T cell and can be targeted to enhance therapeutic antitumor immunity.

CD8+ T cells play a critical role in cancer immune-surveillance and pathogens elimination. However, the effector function of CD8+ T cells may be severely influenced due to inhibitory receptors. Here we identify Siglec-G as a coinhibitory receptor that plays a critical role in limiting the function of CD8+ T cells. Siglec-G is highly expressed on both human and murine tumor-infiltrating T cells, and SiglecG+ T cells enriched in the exhausted T cell subset. CD24-Siglec-G-SHP2 axis negatively regulates PI3K-AKT signaling and impairs metabolic reprogramming in CD8+ T cells and thereby dampens their activation, expansion and cytotoxicity. Genetic ablation of Siglec-G can enhance the efficacy of adoptively transferred T cells and CAR T cells to repress the growth of solid tumors. These results define a key role for Siglec-G in inhibiting CD8+ T cell-dependent responses, which strongly suggested its therapeutic effect in adoptive T cell therapy and tumor immunotherapy. To elucidate the mechanism that mediates the damped function of Siglec-G+ CD8+ T cells, we isolated Siglec-G+ and Siglec-G- OT-I effector cell subsets from LM-OVA infected mice and conducted RNA-seq.