Ablation of prostaglandin E2 signalling through dual receptor knockout in CAR T cells enhances therapeutic efficacy in solid tumours
Menée à l'aide de lignées cellulaires, de modèles murins, d'échantillons tumoraux d'origine humaine et la technologie d'édition CRISPR-Cas9, cette étude démontre que l'ablation de la voie de signalisation de la prostaglandine E2 via la suppression de l'expression des récepteurs EP2 et EP4 augmente l'efficacité des lymphocytes CAR-T
The efficacy of chimeric antigen receptor (CAR) T cell therapy in solid cancers is limited by immunosuppression in the tumour microenvironment (TME). Prostaglandin E2 (PGE2) is a key factor locally inhibiting T cell function. We hypothesized that targeted ablation of PGE2 signalling in CAR T cells may enhance their activity in PGE2-rich solid tumours. Here we generate knockout CAR T cells double deficient for the PGE2 receptors EP2 and EP4 (EP2−/−EP4−/−) by CRISPR–Cas9 engineering. EP2−/−EP4−/− CAR T cells expanded unabatedly in the presence of PGE2. Further, they effectively controlled syngeneic and human xenograft tumour models in vivo, which was accompanied by intratumoural accumulation and persistence of modified T cells. Improved anti-tumour activity was also observed against patient-derived tumour samples from patients with pancreatic ductal adenocarcinoma (PDAC), colorectal (CRC) and neuroendocrine (NET) cancer. Our data uncovers the detrimental impact of PGE2-mediated suppression on CAR T cell efficacy and highlights EP2 and EP4 targeting as a potential strategy.
Nature Biomedical Engineering , article en libre accès, 2026