Targeting branched N-glycans and fucosylation sensitizes ovarian tumors to immune checkpoint blockade
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...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-04-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-47069-y |
| _version_ | 1797219771461140480 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Hao Nie |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-24T12:38:56Z |
| format | Article |
| id | doaj.art-f6c6df012ec140a7a4fd2deb6a11201f |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-04-24T12:38:56Z |
| publishDate | 2024-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-f6c6df012ec140a7a4fd2deb6a11201f2024-04-07T11:24:13ZengNature PortfolioNature Communications2041-17232024-04-0115111610.1038/s41467-024-47069-yTargeting branched N-glycans and fucosylation sensitizes ovarian tumors to immune checkpoint blockadeHao Nie0Pratima Saini1Taito Miyamoto2Liping Liao3Rafal J. Zielinski4Heng Liu5Wei Zhou6Chen Wang7Brennah Murphy8Martina Towers9Tyler Yang10Yuan Qi11Toshitha Kannan12Andrew Kossenkov13Hiroaki Tateno14Daniel T. Claiborne15Nan Zhang16Mohamed Abdel-Mohsen17Rugang Zhang18Department of Experimental Therapeutics, University of Texas MD Anderson Cancer CenterVaccine and Immunotherapy Center, The Wistar InstituteImmunology, Microenvironment and Metastasis Program, The Wistar InstituteDepartment of Experimental Therapeutics, University of Texas MD Anderson Cancer CenterDepartment of Experimental Therapeutics, University of Texas MD Anderson Cancer CenterImmunology, Microenvironment and Metastasis Program, The Wistar InstituteImmunology, Microenvironment and Metastasis Program, The Wistar InstituteDepartment of Experimental Therapeutics, University of Texas MD Anderson Cancer CenterImmunology, Microenvironment and Metastasis Program, The Wistar InstituteDepartment of Experimental Therapeutics, University of Texas MD Anderson Cancer CenterImmunology, Microenvironment and Metastasis Program, The Wistar InstituteDepartment of Bioinformatics & Computational Biology, University of Texas MD Anderson Cancer CenterBioinformatics Facility, The Wistar InstituteGene Expression and Regulation Program, The Wistar InstituteCellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology (AIST)Immunology, Microenvironment and Metastasis Program, The Wistar InstituteImmunology, Microenvironment and Metastasis Program, The Wistar InstituteVaccine and Immunotherapy Center, The Wistar InstituteDepartment of Experimental Therapeutics, University of Texas MD Anderson Cancer CenterAbstract 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.https://doi.org/10.1038/s41467-024-47069-y |
| spellingShingle | 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 Targeting branched N-glycans and fucosylation sensitizes ovarian tumors to immune checkpoint blockade Nature Communications |
| title | Targeting branched N-glycans and fucosylation sensitizes ovarian tumors to immune checkpoint blockade |
| title_full | Targeting branched N-glycans and fucosylation sensitizes ovarian tumors to immune checkpoint blockade |
| title_fullStr | Targeting branched N-glycans and fucosylation sensitizes ovarian tumors to immune checkpoint blockade |
| title_full_unstemmed | Targeting branched N-glycans and fucosylation sensitizes ovarian tumors to immune checkpoint blockade |
| title_short | Targeting branched N-glycans and fucosylation sensitizes ovarian tumors to immune checkpoint blockade |
| title_sort | targeting branched n glycans and fucosylation sensitizes ovarian tumors to immune checkpoint blockade |
| url | https://doi.org/10.1038/s41467-024-47069-y |
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