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

Hao Nie, Pratima Saini, Taito Miyamoto, Liping Liao, Rafal J. Zielinski, Heng Liu, Wei Zhou, Chen Wang, Brennah Murphy, Martina Towers, Tyler Yang, Yuan Qi, Toshitha Kannan, Andrew Kossenkov, Hiroaki Tateno, Daniel T. Claiborne, Nan Zhang, Mohamed Abdel-Mohsen () and Rugang Zhang ()
Additional contact information
Hao Nie: University of Texas MD Anderson Cancer Center
Pratima Saini: The Wistar Institute
Taito Miyamoto: Microenvironment and Metastasis Program, The Wistar Institute
Liping Liao: University of Texas MD Anderson Cancer Center
Rafal J. Zielinski: University of Texas MD Anderson Cancer Center
Heng Liu: Microenvironment and Metastasis Program, The Wistar Institute
Wei Zhou: Microenvironment and Metastasis Program, The Wistar Institute
Chen Wang: University of Texas MD Anderson Cancer Center
Brennah Murphy: Microenvironment and Metastasis Program, The Wistar Institute
Martina Towers: University of Texas MD Anderson Cancer Center
Tyler Yang: Microenvironment and Metastasis Program, The Wistar Institute
Yuan Qi: University of Texas MD Anderson Cancer Center
Toshitha Kannan: The Wistar Institute
Andrew Kossenkov: The Wistar Institute
Hiroaki Tateno: National Institute of Advanced Industrial Science and Technology (AIST)
Daniel T. Claiborne: Microenvironment and Metastasis Program, The Wistar Institute
Nan Zhang: Microenvironment and Metastasis Program, The Wistar Institute
Mohamed Abdel-Mohsen: The Wistar Institute
Rugang Zhang: University of Texas MD Anderson Cancer Center

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-47069-y

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