Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 118, Issue 5, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2015024118
Keywords
Glycobiology; Tumor Immunology; CRISPR Screening
Categories
Funding
- Banting Postdoctoral Fellowship from the Canadian Institutes of Health Research
- NIH [F30CA232541, R01CA227942, U01 CA226051-01A1, R35GM118067, 1S10OD018530, K00 CA21245403]
- National Institute of General Medical Sciences F32 Postdoctoral Fellowship [F32-GM126663-01]
- US NSF Graduate Research Fellowship
- Stanford Graduate Fellowship
- Stanford ChEM-H Chemistry/Biology Interface Predoctoral Training Program
- Stanford School of Medicine Medical Scientist Training Program
- NSF Graduate Research Fellowship
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The study identified key genes required for cell-surface presentation of glycan ligands on leukemia cells using a CRISPRi genomic screening strategy. It revealed a selective interaction between Siglec-7 and the mucin-type glycoprotein CD43, with a specific N-terminal glycopeptide region of CD43 containing clusters of disialylated O-glycan tetrasaccharides forming specific Siglec-7 binding motifs. Knockout or blockade of CD43 in leukemia cells relieves Siglec-7-mediated inhibition of immune killing activity.
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 0-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.
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