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| Home > Publications database > Ablation of prostaglandin E2 signalling through dual receptor knockout in CAR T cells enhances therapeutic efficacy in solid tumours. |
| Home > Publications database > Ablation of prostaglandin E2 signalling through dual receptor knockout in CAR T cells enhances therapeutic efficacy in solid tumours. |
| Journal Article | DKFZ-2026-00331 |
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2026
Nature Research
Tokyo
Abstract: 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.
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