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作者：SCI天天读
SCI
11 May 2024
PGE2 limits effector expansion of tumour-infiltrating stem-like CD8+ T cells
（Nature；IF：64.8）
Lacher SB, Dörr J, de Almeida GP, Hönninger J, Bayerl F, Hirschberger A, Pedde AM, Meiser P, Ramsauer L, Rudolph TJ, Spranger N, Morotti M, Grimm AJ, Jarosch S, Oner A, Gregor L, Lesch S, Michaelides S, Fertig L, Briukhovetska D, Majed L, Stock S, Busch DH, Buchholz VR, Knolle PA, Zehn D, Dangaj Laniti D, Kobold S, Böttcher JP. PGE2 limits effector expansion of tumour-infiltrating stem-like CD8+ T cells. Nature. 2024 Apr 24. doi: 10.1038/s41586-024-07254-x. Epub ahead of print. PMID: 38658748.
Corresponding authors: Sebastian Kobold, Division of Clinical Pharmacology, Department of Medicine IV, LMU University Hospital, Member of the German Center for Lung Research (DZL), LMU Munich, Munich, Germany.Jan P. Böttcher, Institute of Molecular Immunology, School of Medicine and Health, Technical University of Munich (TUM), Munich, Germany.e-mail: j.boettcher@tum.de
Abstract 摘要
Cancer-specific TCF1+ stem-like CD8+ T cells can drive protective anticancer immunity through expansion and effector cell differentiation; however, this response is dysfunctional in tumours. Current cancer immunotherapies can promote anticancer responses through TCF1+ stem-like CD8+ T cells in some but not all patients. This variation points towards currently ill-defined mechanisms that limit TCF1+CD8+ T cell-mediated anticancer immunity. Here we demonstrate that tumour-derived prostaglandin E2 (PGE2) restricts the proliferative expansion and effector differentiation of TCF1+CD8+ T cells within tumours, which promotes cancer immune escape. PGE2 does not affect the priming of TCF1+CD8+ T cells in draining lymph nodes. PGE2 acts through EP2and EP4 (EP2/EP4) receptor signalling in CD8+ T cells to limit the intratumoural generation of early and late effector T cell populations that originate from TCF1+ tumour-infiltrating CD8+ T lymphocytes (TILs). Ablation of EP2/EP4 signalling in cancer-specific CD8+ T cells rescues their expansion and effector differentiation within tumours and leads to tumour elimination in multiple mouse cancer models. Mechanistically, suppression of the interleukin-2 (IL-2) signalling pathway underlies the PGE2-mediated inhibition of TCF1+ TIL responses. Altogether, we uncover a key mechanism that restricts the IL-2 responsiveness of TCF1+ TILs and prevents anticancer T cell responses that originate from these cells. This study identifies the PGE2-EP2/EP4 axis as a molecular target to restore IL-2 responsiveness in anticancer TILs to achieve cancer immune control.
癌症特异性TCF1+干细胞样CD8+T细胞可以通过扩增和效应细胞分化来驱动保护性抗癌免疫；然而，这种反应在肿瘤中是不正常的。目前癌症免疫疗法可以通过TCF1+干细胞样CD8+T细胞促进某些但并非所有患者均具有的抗癌反应。这种变异指向目前定义不清的限制TCF1+CD8+T细胞介导的抗癌免疫的机制。在这里，我们证实了肿瘤衍生的前列腺素E2（PGE2）限制了肿瘤内TCF1+CD8+T细胞的增殖扩张和效应器分化，这促进了癌症免疫逃逸。PGE2不影响引流淋巴结中TCF1+CD8+T细胞的启动。PGE2通过CD8+T细胞中的EP2和EP4（EP2/EP4）受体信号传导发挥作用，以限制肿瘤内产生源自TCF1+肿瘤浸润的CD8+T淋巴细胞（TIL）的早期和晚期效应T细胞群。在多种小鼠癌症模型中，癌症特异性CD8+T细胞中EP2/EP4信号的敲除挽救了其在肿瘤内的扩张和效应器分化，并使肿瘤消除。从机制上讲，白细胞介素2（IL-2）信号通路的抑制是PGE2介导的TCF1+TIL反应抑制的基础。总之，我们揭示了一个关键机制，该机制限制TCF1+TIL的IL-2反应性，并阻止源自这些细胞的抗癌T细胞反应。本研究证实了PGE2-EP2/EP4轴是恢复抗癌TIL中IL-2反应性以实现癌症免疫控制的分子靶点。
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