Targeting branched N-glycans and fucosylation sensitizes ovarian tumors to immune checkpoint blockade

  • Nat Commun. 2024 Apr 2;15(1):2853. doi: 10.1038/s41467-024-47069-y.
Hao Nie  1 ,  Pratima Saini  2 ,  Taito Miyamoto  3 ,  Liping Liao  1 ,  Rafal J Zielinski  1 ,  Heng Liu  3 ,  Wei Zhou  3 ,  Chen Wang  1 ,  Brennah Murphy  3 ,  Martina Towers  1 ,  Tyler Yang  3 ,  Yuan Qi  4 ,  Toshitha Kannan  5 ,  Andrew Kossenkov  6 ,  Hiroaki Tateno  7 ,  Daniel T Claiborne  3 ,  Nan Zhang  3 ,  Mohamed Abdel-Mohsen  8 ,  Rugang Zhang  9  10
Affiliations
  • 1. Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, 77054, USA.
  • 2. Vaccine and Immunotherapy Center, The Wistar Institute, Philadelphia, PA, 19104, USA.
  • 3. Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA, 19104, USA.
  • 4. Department of Bioinformatics & Computational Biology, University of Texas MD Anderson Cancer Center, Houston, TX, 77054, USA.
  • 5. Bioinformatics Facility, The Wistar Institute, Philadelphia, PA, 19104, USA.
  • 6. Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA, 19104, USA.
  • 7. Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki, 305-8566, Japan.
  • 8. Vaccine and Immunotherapy Center, The Wistar Institute, Philadelphia, PA, 19104, USA. [email protected].
  • 9. Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, 77054, USA. [email protected].
  • 10. Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA, 19104, USA. [email protected].
PMID: 38565883 DOI: 10.1038/s41467-024-47069-y
Abstract

Aberrant glycosylation is a crucial strategy employed by Cancer cells to evade cellular immunity. However, it's unclear whether homologous recombination (HR) status-dependent glycosylation can be therapeutically explored. Here, we show that the inhibition of branched N-glycans sensitizes HR-proficient, but not HR-deficient, epithelial ovarian cancers (EOCs) to immune checkpoint blockade (ICB). In contrast to fucosylation whose inhibition sensitizes EOCs to anti-PD-L1 immunotherapy regardless of HR-status, we observe an enrichment of branched N-glycans on HR-proficient compared to HR-deficient EOCs. Mechanistically, BRCA1/2 transcriptionally promotes the expression of MGAT5, the enzyme responsible for catalyzing branched N-glycans. The branched N-glycans on HR-proficient Tumors augment their resistance to anti-PD-L1 by enhancing its binding with PD-1 on CD8+ T cells. In orthotopic, syngeneic EOC models in female mice, inhibiting branched N-glycans using 2-Deoxy-D-glucose sensitizes HR-proficient, but not HR-deficient EOCs, to anti-PD-L1. These findings indicate branched N-glycans as promising therapeutic targets whose inhibition sensitizes HR-proficient EOCs to ICB by overcoming immune evasion.

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