免疫监视
胆碱能的
肝细胞癌
肿瘤免疫学
癌症研究
免疫系统
癌
免疫学
内科学
医学
免疫疗法
肿瘤细胞
作者
Changwen Zheng,Bryan E. Snow,Andrew Elia,Robert Nechanitzky,Carmen Dominguez-Brauer,Shaofeng Liu,Yin Tong,Maureen A. Cox,Enrico Focaccia,Andrew Wakeham,Jillian Haight,Chantal Tobin,Kate Hodgson,Kyle T. Gill,Wei Ma,Thorsten Berger,M Heikenwälder,Mary Saunders,Jérôme Fortin,Suet Yi Leung,Tak W. Mak
出处
期刊:Nature cancer
[Springer Nature]
日期:2023-08-28
卷期号:4 (10): 1437-1454
被引量:3
标识
DOI:10.1038/s43018-023-00624-w
摘要
Abstract 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 Ca 2+ –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.
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