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Disrupting N-glycan expression on tumor cells boosts chimeric antigen receptor T cell efficacy against solid malignancies.
- Source :
- Science Translational Medicine; 1/19/2022, Vol. 14 Issue 628, p1-14, 14p
- Publication Year :
- 2022
-
Abstract
- Immunotherapy with chimeric antigen receptor (CAR)–engineered T cells showed exceptional successes in patients with refractory B cell malignancies. However, first-in-human studies in solid tumors revealed unique hurdles contributing to poor demonstration of efficacy. Understanding the determinants of tumor recognition by CAR T cells should translate into the design of strategies that can overcome resistance. Here, we show that multiple carcinomas express extracellular N-glycans, whose abundance negatively correlates with CAR T cell killing. By knocking out mannoside acetyl-glucosaminyltransferase 5 (MGAT5) in pancreatic adenocarcinoma (PAC), we showed that N-glycans protect tumors from CAR T cell killing by interfering with proper immunological synapse formation and reducing transcriptional activation, cytokine production, and cytotoxicity. To overcome this barrier, we exploited the high metabolic demand of tumors to safely inhibit N-glycans synthesis with the glucose/mannose analog 2-deoxy-d-glucose (2DG). Treatment with 2DG disrupts the N-glycan cover on tumor cells and results in enhanced CAR T cell activity in different xenograft mouse models of PAC. Moreover, 2DG treatment interferes with the PD-1–PD-L1 axis and results in a reduced exhaustion profile of tumor-infiltrating CAR T cells in vivo. The combined 2DG and CAR T cell therapy was successful against multiple carcinomas besides PAC, including those arising from the lung, ovary, and bladder, and with different clinically relevant CAR specificities, such as CD44v6 and CEA. Overall, our results indicate that tumor N-glycosylation regulates the quality and magnitude of CAR T cell responses, paving the way for the rational design of improved therapies against solid malignancies. Going after glycosylation: Chimeric antigen receptor (CAR) T cells have not performed as well against solid tumors as they have against hematological malignancies. One mechanism of resistance that tumor cells used to prevent CAR T cell killing is by glycosylating surface proteins. To reverse this resistance, Greco et al. genetically ablated out mannoside acetyl-glucosaminyltransferase 5 (MGAT5) in tumor cells or treated mice with the glucose/mannose analog 2-deoxy-d-glucose (2DG), both of which disrupted N-glycan expression on the surface of pancreatic adenocarcinoma cells. Disrupting N-glycan synthesis and expression enhanced CAR T cell activity and led to improved killing of not only pancreatic tumors but also tumors of the lung, ovary, and bladder. Together, these findings highlight tumor N-glycosylation as a therapeutic target to improve immunotherapies. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 19466234
- Volume :
- 14
- Issue :
- 628
- Database :
- Complementary Index
- Journal :
- Science Translational Medicine
- Publication Type :
- Academic Journal
- Accession number :
- 159480166
- Full Text :
- https://doi.org/10.1126/scitranslmed.abg3072