胆碱能神经在肿瘤的进展和扩散中起着作用。与其他内脏组织相比，肝脏实质中的胆碱能内神经很难检测到。目前尚不清楚肝癌是否存在任何形式的胆碱能调控。在这里，我们展示了胆碱能T细胞通过支持抗肿瘤免疫应答来抑制肝癌的发展。在小鼠肝细胞癌（HCC）的多击模型中，我们观察到适应性免疫应答的活化以及表达胆碱乙酰转移酶（ChAT）的两个CD4+ T细胞群体的诱导，包括调节性T细胞和功能异常的PD-1+ T细胞。肿瘤抗原推动了这些胆碱能T细胞在HCC中的克隆扩张。T细胞中Chat基因的遗传缺失导致癌前细胞更加普遍和免疫力减退，从而加剧肝癌。在机械上，T细胞内在的胆碱能活性通过限制T细胞抗原受体的钙离子诱导的NFAT信号传导。在没有这种胆碱能调节的情况下，活化过的CD25+调节性T细胞和失控的PD-1+ T细胞损害了HCC的免疫监控。我们的结果揭示了胆碱能T细胞在肝癌免疫生物学中一个以前未被重视的角色。©2023. 作者。

Cholinergic nerves are involved in tumor progression and dissemination. In contrast to other visceral tissues, cholinergic innervation in the hepatic parenchyma is poorly detected. It remains unclear whether there is any form of cholinergic regulation of liver cancer. Here, we show that cholinergic T cells curtail the development of liver cancer by supporting antitumor immune responses. In a mouse multihit model of hepatocellular carcinoma (HCC), we observed activation of the adaptive immune response and induction of two populations of CD4+ T cells expressing choline acetyltransferase (ChAT), including regulatory T cells and dysfunctional PD-1+ T cells. Tumor antigens drove the clonal expansion of these cholinergic T cells in HCC. Genetic ablation of Chat in T cells led to an increased prevalence of preneoplastic cells and exacerbated liver cancer due to compromised antitumor immunity. Mechanistically, the cholinergic activity intrinsic in T cells constrained Ca2+-NFAT signaling induced by T cell antigen receptor engagement. Without this cholinergic modulation, hyperactivated CD25+ T regulatory cells and dysregulated PD-1+ T cells impaired HCC immunosurveillance. Our results unveil a previously unappreciated role for cholinergic T cells in liver cancer immunobiology.© 2023. The Author(s).