Disrupting N-glycan expression on tumor cells boosts chimeric antigen receptor T cell efficacy against solid malignancies
Menée à l'aide de xénogreffes d'adénocarcinome du pancréas sur des modèles murins, cette étude met en évidence l'intérêt d'entraver l'expression des N-glycanes à la surface des cellules cancéreuses pour augmenter l'activité antitumorale des lymphocytes CAR-T
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.