瑞士洛桑大学(UNIL)George Coukos和Denarda Dangaj Laniti共同合作，近期取得重要工作进展。他们研究提出，PGE2通过破坏IL-2信号传导和线粒体功能抑制TIL扩张。相关研究成果2024年4月24日发表在《自然》杂志上。

据介绍，抗原诱导的CD8+T细胞的扩增对于癌症患者肿瘤过滤淋巴细胞（TIL）-过继细胞治疗（ACT）的成功至关重要。白细胞介素-2（IL-2）通过促进扩增和细胞毒性能力，作为CD8⁺细胞毒性T淋巴细胞功能的关键调节因子。因此，有必要了解肿瘤微环境中IL-2感应的机制障碍，以实施重振IL-2反应性和T细胞抗肿瘤反应的策略。

研究人员报道了前列腺素E2（PGE₂），一种已知的肿瘤微环境中免疫反应的负调节因子，以高浓度存在于患者的肿瘤组织中，并通过PGE₂受体EP2和EP4导致人CD8⁺ TIL中IL-2感应受损。从机制上讲，PGE₂通过下调IL-2Rγ_c链抑制TIL中的IL-2传感，导致IL-2Rβ–IL2Rγc膜二聚体的组装缺陷，从而导致IL-2–mTOR适应和PGC1α转录抑制受损，肿瘤反应性TIL中的铁致细胞死亡。在ACT的TIL扩增过程中，PGE₂对EP2和EP4的信号传导被抑制，导致IL-2感应增加，导致肿瘤反应性TIL的增殖增强，并在细胞体内转移后增强肿瘤控制。

总之，这一研究揭示了肿瘤微环境中PGE₂介导的人类TIL损伤的基本特征。这些发现对癌症免疫疗法和细胞治疗具有治疗意义，并能够开发靶向策略来增强TIL中的IL-2感应和扩增IL-2反应，从而促进具有增强治疗潜力的效应T细胞扩增。

附：英文原文

Title: PGE2 inhibits TIL expansion by disrupting IL-2 signalling and mitochondrial function

Author: Morotti, Matteo, Grimm, Alizee J., Hope, Helen Carrasco, Arnaud, Marion, Desbuisson, Mathieu, Rayroux, Nicolas, Barras, David, Masid, Maria, Murgues, Baptiste, Chap, Bovannak S., Ongaro, Marco, Rota, Ioanna A., Ronet, Catherine, Minasyan, Aspram, Chiffelle, Johanna, Lacher, Sebastian B., Bobisse, Sara, Murgues, Clment, Ghisoni, Eleonora, Ouchen, Khaoula, Bou Mjahed, Ribal, Benedetti, Fabrizio, Abdellaoui, Naoill, Turrini, Riccardo, Gannon, Philippe O., Zaman, Khalil, Mathevet, Patrice, Lelievre, Loic, Crespo, Isaac, Conrad, Marcus, Verdeil, Gregory, Kandalaft, Lana E., Dagher, Julien, Corria-Osorio, Jesus, Doucey, Marie-Agnes, Ho, Ping-Chih, Harari, Alexandre, Vannini, Nicola, Bttcher, Jan P., Dangaj Laniti, Denarda, Coukos, George

Issue&Volume: 2024-04-24

Abstract: Expansion of antigen-experienced CD8+ T cells is critical for the success of tumour-infiltrating lymphocyte (TIL)-adoptive cell therapy (ACT) in patients with cancer1. Interleukin-2 (IL-2) acts as a key regulator of CD8+ cytotoxic T lymphocyte functions by promoting expansion and cytotoxic capability2,3. Therefore, it is essential to comprehend mechanistic barriers to IL-2 sensing in the tumour microenvironment to implement strategies to reinvigorate IL-2 responsiveness and T cell antitumour responses. Here we report that prostaglandin E2 (PGE2), a known negative regulator of immune response in the tumour microenvironment4,5, is present at high concentrations in tumour tissue from patients and leads to impaired IL-2 sensing in human CD8+ TILs via the PGE2 receptors EP2 and EP4. Mechanistically, PGE2 inhibits IL-2 sensing in TILs by downregulating the IL-2Rγc chain, resulting in defective assembly of IL-2Rβ–IL2Rγc membrane dimers. This results in impaired IL-2–mTOR adaptation and PGC1α transcriptional repression, causing oxidative stress and ferroptotic cell death in tumour-reactive TILs. Inhibition of PGE2 signalling to EP2 and EP4 during TIL expansion for ACT resulted in increased IL-2 sensing, leading to enhanced proliferation of tumour-reactive TILs and enhanced tumour control once the cells were transferred in vivo. Our study reveals fundamental features that underlie impairment of human TILs mediated by PGE2 in the tumour microenvironment. These findings have therapeutic implications for cancer immunotherapy and cell therapy, and enable the development of targeted strategies to enhance IL-2 sensing and amplify the IL-2 response in TILs, thereby promoting the expansion of effector T cells with enhanced therapeutic potential. Prostaglandin E2 from the tumour microenvironment impairs interleukin-2 sensing by tumour-infiltrating lymphocytes, restricting proliferative response and promoting T cell death via metabolic impairment and ferroptosis. 

DOI: 10.1038/s41586-024-07352-w

Source: https://www.nature.com/articles/s41586-024-07352-w