Genome-wide CRISPR screens reveal a specific ligand for the glycan-binding immune checkpoint receptor Siglec-7
Wisnovsky S, Möckl L, Malaker SA, Pedram K, Hess GT, Riley NM, Gray MA, Smith BA, Bassik MC, Moerner WE, Bertozzi CR (2021)
Publication Type: Journal article
Publication year: 2021
Journal
Book Volume: 118
Article Number: e2015024118
Journal Issue: 5
Abstract
Glyco-immune checkpoint receptors, molecules that inhibit immune cell activity following binding to glycosylated cell-surface antigens, are emerging as attractive targets for cancer immunotherapy. Defining biologically relevant ligands that bind and activate such receptors, however, has historically been a significant challenge. Here, we present a CRISPRi genomic screening strategy that allowed unbiased identification of the key genes required for cell-surface presentation of glycan ligands on leukemia cells that bind the glyco-immune checkpoint receptors Siglec-7 and Siglec-9. This approach revealed a selective interaction between Siglec-7 and the mucin-type glycoprotein CD43. Further work identified a specific N-terminal glycopeptide region of CD43 containing clusters of disialylated O-glycan tetrasaccharides that form specific Siglec-7 binding motifs. Knockout or blockade of CD43 in leukemia cells relieves Siglec-7-mediated inhibition of immune killing activity. This work identifies a potential target for immune checkpoint blockade therapy and represents a generalizable approach to dissection of glycan–receptor interactions in living cells.
Involved external institutions
United States (USA) (US)How to cite
APA:
Wisnovsky, S., Möckl, L., Malaker, S.A., Pedram, K., Hess, G.T., Riley, N.M.,... Bertozzi, C.R. (2021). Genome-wide CRISPR screens reveal a specific ligand for the glycan-binding immune checkpoint receptor Siglec-7. Proceedings of the National Academy of Sciences of the United States of America, 118(5). https://doi.org/10.1073/pnas.2015024118
MLA:
Wisnovsky, Simon, et al. "Genome-wide CRISPR screens reveal a specific ligand for the glycan-binding immune checkpoint receptor Siglec-7." Proceedings of the National Academy of Sciences of the United States of America 118.5 (2021).
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