Abstract

Abstract Aberrant glycans on tumor cell surface contribute to immune escape. The purpose of this study is to establish novel immunotherapeutic strategies for HGSOC tumors by targeting glycans-mediated immune escape in high-grade serous ovarian cancer (HGSOC). Here, we performed in vivo screens targeting 96 glycan structures among a series of mouse HGSOC tumors with different genotypes. We identified β1, 6-GlcNAc branched N-glycan as a major determinant of immune escape in a homologous recombination (HR)-proficiency dependent manner in HGSOCs. Mechanistically, BRCA1/2 transcriptionally suppresses the expression of MGAT5 that produces β1, 6-GlcNAc branched glycans. Using in vitro T cell killing assay, we observed that removal of β1, 6-GlcNAc branched glycans by a small molecule inhibitor or genetically knocking down MGAT5, sensitizes HR-proficient human HGSOC cells to T cells assault. Consistently, using orthotopic syngeneic mouse models, we observed that inhibition of β1, 6-GlcNAc branched glycans sensitizes and synergizes with anti-PD-L1 in HR-proficient, but not HR-deficient HGSOCs. In summary, we identified β1, 6-GlcNAc branched N-glycan as a key mediator of immune escape in HR-proficient HGSOCs. Our findings indicate that MGAT5 represents a therapeutic target to overcome immune escape in a HR-status dependent manner and inhibition of β1, 6-GlcNAc branched glycans sensitizes HR-proficient HGSOCs to immune checkpoint blockades. Citation Format: Hao Nie, Pratima Saini, Heng Liu, Wei Zhou, Chen Wang, Daniel Claiborne, Nan Zhang, Mohamed Abdel-Mohsen, Rugang Zhang. Targeting cancer glycomes sensitizes ovarian tumors to immunotherapy [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr B076.

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