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MYC-driven synthesis of Siglec ligands is a glycoimmune checkpoint

Benjamin A H Smith1,2, Anja Deutzmann3, Kristina M Correa4

  • 1Sarafan ChEM-H, Stanford University, Stanford, CA 94305.

Proceedings of the National Academy of Sciences of the United States of America
|March 10, 2023
PubMed

Insights

The MYC oncogene drives cancer immune evasion by controlling the production of disialyl-T, a "don't eat me" signal that engages Siglec receptors on immune cells. This discovery offers new targets for cancer immunotherapy.

Area of Science:

  • Immunology
  • Glycobiology
  • Oncology

Background:

  • Siglecs (sialic acid-binding immunoglobulin-like lectins) are glycoimmune checkpoint receptors that inhibit immune cell activation.
  • The mechanisms controlling Siglec ligand production on cancer cells, crucial for tumor immune evasion, are not well understood.

Purpose of the Study:

  • To investigate the role of the MYC oncogene in regulating Siglec ligand production and its impact on tumor immune evasion.
  • To identify the specific glycan ligand and its associated enzymes involved in MYC-driven immune suppression.

Main Methods:

  • Glycomics and RNA-sequencing of mouse tumors to analyze gene expression and glycan profiles.
  • In vivo mouse models and analysis of primary human leukemias to validate findings.
  • Functional assays to assess the interaction between disialyl-T and Siglec receptors.

Main Results:

  • The MYC oncogene was found to causally regulate the expression of the sialyltransferase ST6GALNAC4, leading to the production of the disialyl-T glycan.
  • Disialyl-T acts as a "don't eat me" signal by binding to macrophage Siglec-E (mouse) or Siglec-7 (human), inhibiting cancer cell clearance.
  • High MYC and ST6GALNAC4 expression correlates with high-risk cancers and reduced myeloid cell infiltration in tumors.

Conclusions:

  • MYC oncogene regulates cancer cell glycosylation to promote immune evasion by inducing disialyl-T.
  • Disialyl-T functions as a glycoimmune checkpoint ligand, making it a potential target for antibody-based therapies.
  • ST6GALNAC4, the enzyme synthesizing disialyl-T, is a potential target for small molecule-based immunotherapies.
Keywords:
MYCSiglecglycosylationoncogene

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