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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.
摘要：
具有抗原的CD8T细胞的扩增对于癌症患者的肿瘤浸润淋巴细胞（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2,3充当CD8+细胞毒性T淋巴细胞功能的关键调节因子。因此,理解肿瘤微环境中IL-2感知的机制障碍对于实施策略以重振IL-2应答和T细胞抗肿瘤应答是至关重要的。在这里，我们报道了前列腺素E2（PGE2），肿瘤微环境4,5中已知的免疫应答的负调节因子以高浓度存在于来自患者的肿瘤组织中,并通过PGE2受体EP2和EP4导致人CD8+TIL中的IL-2感知受损。机械上,PGE2通过下调IL-2Rγc链抑制TIL中的IL-2传感，导致IL-2Rβ-IL2Rγc膜二聚体的组装缺陷。这导致受损的IL-2-mTOR适应和PGC1α转录抑制，在肿瘤反应性TIL中引起氧化应激和铁细胞死亡。在ACT的TIL扩增期间PGE2信号对EP2和EP4的抑制导致IL-2感知增加,导致肿瘤反应性TIL的增殖增强，并在体内转移细胞后增强肿瘤控制。我们的研究揭示了肿瘤微环境中PGE2介导的人类TILs受损的基本特征。这些发现对癌症免疫疗法和细胞疗法具有治疗意义。并能够开发有针对性的策略来增强IL-2感知并放大TIL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。
