Targeting branched N-glycans and fucosylation sensitizes ovarian tumors to immune checkpoint blockade
Hao Nie, Pratima Saini, Taito Miyamoto, Liping Liao, Rafał Zieliński, Heng Liu, Wei Zhou, Chen Wang, Brennah Murphy, Martina Towers, Tyler T. Yang, Yuan Qi, Toshitha Kannan, Andrew V. Kossenkov, Hiroaki Tateno, Daniel T. Claiborne, Nan Zhang, Mohamed Abdel‐Mohsen, Rugang Zhang
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.