Journal article
MYC-driven synthesis of Siglec ligands is a glycoimmune checkpoint
Proceedings of the National Academy of Sciences - PNAS, Vol.120(11), e2215376120
03/14/2023
DOI: 10.1073/pnas.2215376120
PMCID: PMC10089186
PMID: 36897988
Abstract
The Siglecs (sialic acid-binding immunoglobulin-like lectins) are glycoimmune checkpoint receptors that suppress immune cell activation upon engagement of cognate sialoglycan ligands. The cellular drivers underlying Siglec ligand production on cancer cells are poorly understood. We find the
oncogene causally regulates Siglec ligand production to enable tumor immune evasion. A combination of glycomics and RNA-sequencing of mouse tumors revealed the
oncogene controls expression of the sialyltransferase
and induces a glycan known as disialyl-T. Using in vivo models and primary human leukemias, we find that disialyl-T functions as a "don't eat me" signal by engaging macrophage Siglec-E in mice or the human ortholog Siglec-7, thereby preventing cancer cell clearance. Combined high expression of
and
identifies patients with high-risk cancers and reduced tumor myeloid infiltration. MYC therefore regulates glycosylation to enable tumor immune evasion. We conclude that disialyl-T is a glycoimmune checkpoint ligand. Thus, disialyl-T is a candidate for antibody-based checkpoint blockade, and the disialyl-T synthase ST6GALNAC4 is a potential enzyme target for small molecule-mediated immune therapy.
Details
- Title: Subtitle
- MYC-driven synthesis of Siglec ligands is a glycoimmune checkpoint
- Creators
- Benjamin A H Smith - Stanford UniversityAnja Deutzmann - Stanford UniversityKristina M Correa - Stanford UniversityCorleone S Delaveris - Stanford UniversityRenumathy Dhanasekaran - Stanford UniversityChristopher G Dove - Stanford UniversityDelaney K Sullivan - Stanford UniversitySimon Wisnovsky - University of British ColumbiaJessica C Stark - Department of Chemistry, Stanford University, Stanford, CA 94305John V Pluvinage - University of California, San FranciscoSrividya Swaminathan - Stanford UniversityNicholas M Riley - Department of Chemistry, Stanford University, Stanford, CA 94305Anand Rajan - University of Iowa, PathologyRavindra Majeti - Stanford UniversityDean W Felsher - Stanford UniversityCarolyn R Bertozzi - Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.120(11), e2215376120
- DOI
- 10.1073/pnas.2215376120
- PMID
- 36897988
- PMCID
- PMC10089186
- NLM abbreviation
- Proc Natl Acad Sci U S A
- ISSN
- 0027-8424
- eISSN
- 1091-6490
- Grant note
- T32 GM007365 / NIGMS NIH HHS R35 CA253180 / NCI NIH HHS F32 CA250324 / NCI NIH HHS F30 CA232541 / NCI NIH HHS K08 CA222676 / NCI NIH HHS R01 CA208735 / NCI NIH HHS F30 AG060638 / NIA NIH HHS U01 CA188383 / NCI NIH HHS K00 CA212454 / NCI NIH HHS S10 RR027431 / NCRR NIH HHS R01 CA184384 / NCI NIH HHS R01 CA227942 / NCI NIH HHS R01 CA170378 / NCI NIH HHS
- Language
- English
- Date published
- 03/14/2023
- Academic Unit
- Pathology
- Record Identifier
- 9984473209502771
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