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<p>The efficacy of chimeric antigen receptor (CAR) T cell therapy in solid cancers is limited by immunosuppression in the tumour microenvironment (TME). Prostaglandin E<sub>2</sub> (PGE<sub>2</sub>) is a key factor locally inhibiting T cell function. We hypothesized that targeted ablation of PGE<sub>2</sub> signalling in CAR T cells may enhance their activity in PGE<sub>2</sub>-rich solid tumours. Here we generate knockout CAR T cells double deficient for the PGE<sub>2</sub> receptors EP2 and EP4 (EP2<sup>−/−</sup>EP4<sup>−/−</sup>) by CRISPR–Cas9 engineering. EP2<sup>−/−</sup>EP4<sup>−/−</sup> CAR T cells expanded unabatedly in the presence of PGE<sub>2</sub>. 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<sub>2</sub>-mediated suppression on CAR T cell efficacy and highlights EP2 and EP4 targeting as a potential strategy.</p>

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Ablation of prostaglandin E2 signalling through dual receptor knockout in CAR T cells enhances therapeutic efficacy in solid tumours

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月11日

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  • Janina Dörr,
  • Lisa Gregor,
  • Sebastian B. Lacher,
  • Arman Oner,
  • Yi Sun,
  • Ignazio Piseddu,
  • Luisa Fertig,
  • Sebastijan Spajic,
  • Stefanie Lesch,
  • Stefanos Michaelides,
  • Matthias Seifert,
  • Adrian Gottschlich,
  • Natasha Samson,
  • Lina Majed,
  • Daria Briukhovetska,
  • Donjetë Simnica,
  • Viktoria Hartmann,
  • Kathrin Gabriel,
  • Sonia Cohen,
  • Genevieve M. Boland,
  • David Andreu-Sanz,
  • Emanuele Carlini,
  • Sophia Stock,
  • Anne Holtermann,
  • Philipp Jie Müller,
  • Thaddäus Strzalkowski,
  • Marcel P. Trefny,
  • Stefan Endres,
  • Russell W. Jenkins,
  • Jan P. Böttcher,
  • Sebastian Kobold

摘要

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.