2. Academic Validation
  3. Targeting branched N-glycans and fucosylation sensitizes ovarian tumors to immune checkpoint blockade

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

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. mmohsen@wistar.org.
  • 9 Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, 77054, USA. rzhang11@mdanderson.org.
  • 10 Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA, 19104, USA. rzhang11@mdanderson.org.
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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