PDF(Pubmed)
Abstract：
Cancer-specific TCF1+ stem-like CD8+ T cells can drive protective anticancer immunity through expansion and effector cell differentiation1-4; however, this response is dysfunctional in tumours. Current cancer immunotherapies2,5-9 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 EP2 and 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.
摘要：
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驱动保护性抗癌免疫1-4;然而，这种反应在肿瘤中是功能失调的。目前的癌症免疫治疗2,5-9可以通过TCF1+干细胞样CD8+T细胞在一些但不是所有患者中促进抗癌反应。这种变化指向限制TCF1+CD8+T细胞介导的抗癌免疫的目前不明确的机制。在这里，我们证明了肿瘤来源的前列腺素E2（PGE2）限制了肿瘤内TCF1CD8T细胞的增殖扩增和效应子分化，促进癌症免疫逃逸。PGE2不影响引流淋巴结中TCF1+CD8+T细胞的引发。PGE2通过CD8+T细胞中的EP2和EP4(EP2/EP4)受体信号传导起作用,以限制源自TCF1+肿瘤浸润性CD8+T淋巴细胞(TIL)的早期和晚期效应T细胞群的肿瘤内生成。癌症特异性CD8+T细胞中EP2/EP4信号传导的消融挽救了它们在肿瘤内的扩增和效应子分化,并导致多种小鼠癌症模型中的肿瘤消除。机械上,白介素-2(IL-2)信号通路的抑制是PGE2介导的TCF1+TIL应答抑制的基础.总之,我们揭示了限制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轴作为分子靶标，以恢复抗癌TIL中的IL-2反应性以实现癌症免疫控制。
