Source data: Ablation of prostaglandin E2-signaling through dual receptor knock-out in CAR T cells enhances therapeutic efficacy in solid tumors

This entry contains the datasets associated with the publication "Ablation of prostaglandin E2-signaling through dual receptor knock-out in CAR T cells enhances therapeutic efficacy in solid tumors".

Abstract:
The efficacy of chimeric antigen receptor (CAR) T cell therapy in solid cancers is limited by immunosuppression in the tumor microenvironment (TME). Prostaglandin E2 (PGE2) is a key factor locally inhibiting T cell function. We hypothesized that targeted ablation of PGE2 signaling in CAR T cells may enhance their activity in PGE2-rich solid tumors.
Here, we generated 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 tumor models in vivo, which was accompanied by intratumoral accumulation and persistence of modified T cells. Improved anti-tumor activity was also observed against patient-derived tumor samples from pancreatic ductal adenocarcinoma (PDAC), colorectal (CRC) and neuroendocrine (NET) cancer patients. Our data uncovers the detrimental impact of PGE2-mediated suppression on CAR T cell efficacy and highlights EP2 and EP4 targeting as potential strategy.