Genome-wide CRISPR screens reveal a specific ligand for the glycan-binding immune checkpoint receptor Siglec-7

Significance Cancer cells are frequently coated with chains of sugar molecules (glycans) that bind to inhibitory immune receptors, leading to suppression of anticancer immunity. While blocking these interactions may be therapeutically beneficial, the specific glycoprotein ligands that engage such receptors are often complex and difficult to characterize. To solve this problem, we used unbiased genome-wide screening to identify genes required for cell-surface presentation of ligands that bind members of the Siglec immune receptor family. This approach led to identification of the glycoprotein CD43 as a highly specific ligand for Siglec-7. Blocking the interaction between CD43 and Siglec-7 sensitizes leukemia cells to immune cell lysis, implying that targeting the CD43/Siglec-7 checkpoint could be therapeutically beneficial.