肿瘤细胞治疗研究
英文原题：Ablation of prostaglandin E(2) signalling through dual receptor knockout in CAR T cells enhances therapeutic efficacy in solid tumours.
嵌合抗原受体（CAR）T 细胞治疗在实体瘤中的疗效受到肿瘤微环境（TME）中免疫抑制的限制。
嵌合抗原受体（CAR）T细胞治疗实体瘤的疗效受到肿瘤微环境（TME）免疫抑制限制。前列腺素E2（PGE2）是局部抑制T细胞功能的关键因素。研究者假设，靶向清除CAR-T细胞中的PGE2信号可增强其在PGE2丰富实体瘤中的活性。本研究通过CRISPR-Cas9工程化构建同时缺失PGE2受体EP2和EP4的CAR-T细胞（EP2−/−EP4−/−）。在PGE2存在时，EP2−/−EP4−/− CAR-T仍可持续扩增；此外，该细胞在体内有效控制同系肿瘤和人体异种移植肿瘤模型，并伴有改造T细胞在肿瘤内蓄积和持续存在。对来自胰腺导管腺癌（PDAC）、结直肠癌（CRC）及神经内分泌肿瘤（NET）患者的肿瘤样本，也观察到抗肿瘤活性提高。研究揭示PGE2介导的抑制会损害CAR-T疗效，并提示靶向EP2和EP4可能是一种治疗策略。
The efficacy of chimeric antigen receptor (CAR) T cell therapy in solid cancers is limited by immunosuppression in the tumour microenvironment (TME). Prostaglandin E 2 (PGE 2 ) is a key factor locally inhibiting T cell function. We hypothesized that targeted ablation of PGE 2 signalling in CAR T cells may enhance their activity in PGE 2 -rich solid tumours. Here we generate knockout CAR T cells double deficient for the PGE 2 receptors EP2 and EP4 (EP2 -/- EP4 -/- ) by CRISPR-Cas9 engineering. EP2 -/- EP4 -/- CAR T cells expanded unabatedly in the presence of PGE 2 . 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 PGE 2 -mediated suppression on CAR T cell efficacy and highlights EP2 and EP4 targeting as a potential strategy.
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