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

Author:

Wisnovsky SimonORCID,Möckl LeonhardORCID,Malaker Stacy A.ORCID,Pedram KayvonORCID,Hess Gaelen T.,Riley Nicholas M.ORCID,Gray Melissa A.,Smith Benjamin A. H.ORCID,Bassik Michael C.,Moerner W. E.ORCID,Bertozzi Carolyn R.ORCID

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.

Funder

HHS | NIH | National Cancer Institute

HHS | NIH | National Institute of General Medical Sciences

HHS | National Institutes of Health

Gouvernement du Canada | CIHR | Institute of Cancer Research

National Science Foundation

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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