Faculty, Staff and Student Publications
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
DOI
10.1038/s41467-024-47069-y
PMID
38565883
PMCID
PMC10987604
PubMedCentral® Posted Date
April 2024
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Included in
Bioinformatics Commons, Biomedical Informatics Commons, Medical Sciences Commons, Obstetrics and Gynecology Commons, Oncology Commons, Women's Health Commons
Comments
Associated Data