ABOUT THE COVER
Altered tumor glycosylation is now appreciated to have an immunosuppressive role, whereby immune responses can be downregulated via activity of Siglecs, cell surface proteins that bind sialic acid–containing glycans. Although Siglecs are expressed on some immune cells, T cells rarely express them. Haas et al. report that in melanoma, the majority of tumor-infiltrating, but not circulating, CD8⁺ T cells express Siglec-9. This subset of Siglec-9⁺ T cells is highly cytotoxic and proliferative. However, engagement of siglec-9 inhibits the effector functions of the Siglec-9–expressing CD8⁺ T cells, due to dephosphorylation of the TCR pathway molecules by the SHP-1 phosphatase, which dampens TCR signaling. The majority of primary and metastatic melanoma cells express Siglec-9 ligands. Thus, Siglec-9 receptor-ligand interactions are a glycosylation-dependent inhibitory circuit that suppresses immune responses in the tumor microenvironment. These data suggest that blocking this interaction may enhance antitumor responses, while also confining CD8⁺ T-cell activation to the tumor microenvironment. Read more in this issue on page 707. Original image from Fig. 2A. Artwork by Lewis Long.