PGE2 inhibits TIL expansion by disrupting IL-2 signalling and mitochondrial function,Nature

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PGE2 inhibits TIL expansion by disrupting IL-2 signalling and mitochondrial function
Nature ( IF 50.5 ) Pub Date : 2024-04-24 , DOI: 10.1038/s41586-024-07352-w
Matteo Morotti _{1,

2,

3} , Alizee J Grimm _{1,

2,

3} , Helen Carrasco Hope _{1,

2} , Marion Arnaud _{1,

2,

3} , Mathieu Desbuisson _{1,

2,

3} , Nicolas Rayroux _{1,

2,

3} , David Barras _{1,

2,

3} , Maria Masid _{1,

2,

3} , Baptiste Murgues _{1,

2,

3} , Bovannak S Chap _{1,

2,

3} , Marco Ongaro _{1,

2} , Ioanna A Rota _{1,

3} , Catherine Ronet _{1,

3} , Aspram Minasyan _{1,

2,

3} , Johanna Chiffelle _{1,

2,

3} , Sebastian B Lacher ₄ , Sara Bobisse _{1,

3} , Clément Murgues ₅ , Eleonora Ghisoni _{1,

2,

3} , Khaoula Ouchen _{1,

3} , Ribal Bou Mjahed _{1,

2} , Fabrizio Benedetti _{1,

2} , Naoill Abdellaoui _{1,

2,

3} , Riccardo Turrini ₁ , Philippe O Gannon ₅ , Khalil Zaman ₂ , Patrice Mathevet ₆ , Loic Lelievre ₆ , Isaac Crespo _{1,

2,

3} , Marcus Conrad ₇ , Gregory Verdeil _{1,

2} , Lana E Kandalaft ₅ , Julien Dagher ₈ , Jesus Corria-Osorio _{1,

3} , Marie-Agnes Doucey ₁ , Ping-Chih Ho _{1,

2} , Alexandre Harari _{1,

2,

3} , Nicola Vannini _{1,

2} , Jan P Böttcher ₄ , Denarda Dangaj Laniti _{1,

2,

3} , George Coukos _{1,

2,

3}

Affiliation

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 capability^2,3. 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 microenvironment^4,5, 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-2Rγ_c chain, resulting in defective assembly of IL-2Rβ–IL2Rγ_c 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.

中文翻译：

PGE2 通过破坏 IL-2 信号传导和线粒体功能来抑制 TIL 扩增

抗原经历的 CD8⁺ T 细胞的扩增对于癌症患者肿瘤浸润淋巴细胞（TIL）过继细胞疗法（ACT）的成功至关重要¹。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^2,3。因此，必须了解肿瘤微环境中 IL-2 感应的机制障碍，以实施重新激发 IL-2 反应和 T 细胞抗肿瘤反应的策略。在这里，我们报道了前列腺素 E2 （PGE₂）是肿瘤微环境中已知的免疫反应负调节因子^4,5，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 中的 IL-2 感应受损。从机制上讲，PGE₂ 通过下调 IL-2Rγ_c 链来抑制 TIL 中的 IL-2 感应，导致 IL-2Rβ-IL2Rγ_c 膜二聚体组装缺陷。这导致 IL-2-mTOR 适应受损和 PGC1α 转录抑制，导致肿瘤反应性 TIL 中的氧化应激和铁死亡细胞。在 ACT 的 TIL 扩增过程中抑制 PGE₂ 向 EP2 和 EP4 的信号传导导致 IL-2 感应增加，一旦细胞在体内转移，导致肿瘤反应性 TIL 的增殖增强和肿瘤控制增强。我们的研究揭示了 PGE₂ 在肿瘤微环境中介导的人类 TILs 损伤的基本特征。这些发现对癌症免疫治疗和细胞治疗具有治疗意义，并有助于开发靶向策略以增强 IL-2 感应并放大 TILs 中的 IL-2 反应，从而促进具有增强治疗潜力的效应 T 细胞的扩增。

更新日期：2024-04-25

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