Targeting Branched N-glycans and Fucosylation Sensitizes Ovarian Tumors to Immune Checkpoint Blockade

Authors

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
Rugang Zhang

Publication Date

4-2-2024

Journal

Nature Communications

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.

Keywords

Humans, Female, Animals, Mice, BRCA1 Protein, Immune Checkpoint Inhibitors, CD8-Positive T-Lymphocytes, Glycosylation, BRCA2 Protein, Ovarian Neoplasms, Carcinoma, Ovarian Epithelial, B7-H1 Antigen, Ovarian cancer, Ovarian cancer, Tumour immunology, Cancer immunotherapy

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Associated Data

PMID: 38565883