小柯机器人

德国慕尼黑工业大学Jan P. Böttcher课题组发现，PGE₂限制肿瘤浸润干细胞样CD8⁺ T细胞的效应扩增。相关论文于2024年4月24日在线发表在《自然》杂志上。

研究人员证明了肿瘤衍生的前列腺素E2（PGE₂）会限制肿瘤内TCF1⁺ CD8⁺ T细胞的增殖扩张和效应分化，从而促进癌症免疫逃逸。PGE₂不会影响引流淋巴结中TCF1⁺ CD8⁺ T细胞的活化。PGE₂通过CD8⁺ T细胞中的EP₂和EP₄（EP₂/EP₄）受体信号发挥作用，限制肿瘤内早期和晚期效应T细胞群的生成，这些效应T细胞群源自TCF1⁺肿瘤浸润的CD8⁺ T淋巴细胞（TIL）。消减癌症特异性CD8⁺ T细胞中的EP₂/EP₄信号可挽救它们在肿瘤内的扩增和效应分化，并在多种小鼠癌症模型中消除肿瘤。

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，研究人员发现了一种限制TCF1⁺ TIL的IL-2反应性并阻止源自这些细胞的抗癌T细胞反应的关键机制。这项研究确定了PGE₂-EP₂/EP₄轴是恢复抗癌TIL IL-2反应性以实现癌症免疫控制的分子靶点。

据介绍，癌症特异性TCF1⁺干细胞样CD8⁺ T细胞可通过扩增和效应细胞分化驱动保护性抗癌免疫；然而，这种反应在肿瘤中功能失调。目前的癌症免疫疗法可通过TCF1⁺干细胞样CD8⁺ T细胞促进部分而非所有患者的抗癌反应。这种差异表明，目前尚未明确的机制限制了TCF1⁺ CD8⁺ T细胞介导的抗癌免疫。

附：英文原文

Title: PGE2 limits effector expansion of tumour-infiltrating stem-like CD8+ T cells

Author: Lacher, Sebastian B., Drr, Janina, de Almeida, Gustavo P., Hnninger, Julian, Bayerl, Felix, Hirschberger, Anna, Pedde, Anna-Marie, Meiser, Philippa, Ramsauer, Lukas, Rudolph, Thomas J., Spranger, Nadine, Morotti, Matteo, Grimm, Alizee J., Jarosch, Sebastian, Oner, Arman, Gregor, Lisa, Lesch, Stefanie, Michaelides, Stefanos, Fertig, Luisa, Briukhovetska, Daria, Majed, Lina, Stock, Sophia, Busch, Dirk H., Buchholz, Veit R., Knolle, Percy A., Zehn, Dietmar, Dangaj Laniti, Denarda, Kobold, Sebastian, Bttcher, Jan P.

Issue&Volume: 2024-04-24

Abstract: Cancer-specific TCF1+ stem-like CD8+ Tcells can drive protective anticancer immunity through expansion and effector cell differentiation1,2,3,4; however, this response is dysfunctional in tumours. Current cancer immunotherapies2,5,6,7,8,9 can promote anticancer responses through TCF1+ stem-like CD8+ Tcells in some but not all patients. This variation points towards currently ill-defined mechanisms that limit TCF1+CD8+ Tcell-mediated anticancer immunity. Here we demonstrate that tumour-derived prostaglandinE2 (PGE2) restricts the proliferative expansion and effector differentiation of TCF1+CD8+ Tcells within tumours, which promotes cancer immune escape. PGE2 does not affect the priming of TCF1+CD8+ Tcells in draining lymph nodes. PGE2 acts through EP2 and EP4 (EP2/EP4) receptor signalling in CD8+ Tcells to limit the intratumoural generation of early and late effector Tcell populations that originate from TCF1+ tumour-infiltrating CD8+ Tlymphocytes (TILs). Ablation of EP2/EP4 signalling in cancer-specific CD8+ Tcells 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 Tcell 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.

DOI: 10.1038/s41586-024-07254-x

Source: https://www.nature.com/articles/s41586-024-07254-x

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
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