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N-glycosylation by Mgat5 imposes a targetable constraint on immune-mediated tumor clearance.
- Source :
-
JCI insight [JCI Insight] 2024 May 23; Vol. 9 (12). Date of Electronic Publication: 2024 May 23. - Publication Year :
- 2024
-
Abstract
- The regulated glycosylation of the proteome has widespread effects on biological processes that cancer cells can exploit. Expression of N-acetylglucosaminyltransferase V (encoded by Mgat5 or GnT-V), which catalyzes the addition of β1,6-linked N-acetylglucosamine to form complex N-glycans, has been linked to tumor growth and metastasis across tumor types. Using a panel of murine pancreatic ductal adenocarcinoma (PDAC) clonal cell lines that recapitulate the immune heterogeneity of PDAC, we found that Mgat5 is required for tumor growth in vivo but not in vitro. Loss of Mgat5 results in tumor clearance that is dependent on T cells and dendritic cells, with NK cells playing an early role. Analysis of extrinsic cell death pathways revealed Mgat5-deficient cells have increased sensitivity to cell death mediated by the TNF superfamily, a property that was shared with other non-PDAC Mgat5-deficient cell lines. Finally, Mgat5 knockout in an immunotherapy-resistant PDAC line significantly decreased tumor growth and increased survival upon immune checkpoint blockade. These findings demonstrate a role for N-glycosylation in regulating the sensitivity of cancer cells to T cell killing through classical cell death pathways.
- Subjects :
- Animals
Humans
Mice
Cell Line, Tumor
Dendritic Cells immunology
Dendritic Cells metabolism
Glycosylation
Killer Cells, Natural immunology
Killer Cells, Natural metabolism
Mice, Knockout
T-Lymphocytes immunology
T-Lymphocytes metabolism
Carcinoma, Pancreatic Ductal immunology
Carcinoma, Pancreatic Ductal pathology
Carcinoma, Pancreatic Ductal metabolism
Carcinoma, Pancreatic Ductal genetics
N-Acetylglucosaminyltransferases metabolism
N-Acetylglucosaminyltransferases genetics
Pancreatic Neoplasms immunology
Pancreatic Neoplasms pathology
Pancreatic Neoplasms metabolism
Pancreatic Neoplasms genetics
Subjects
Details
- Language :
- English
- ISSN :
- 2379-3708
- Volume :
- 9
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- JCI insight
- Publication Type :
- Academic Journal
- Accession number :
- 38912584
- Full Text :
- https://doi.org/10.1172/jci.insight.178804