文章目录

肿瘤特异性胆碱能CD4+ T淋巴细胞引导肝细胞癌的免疫监测

原文发布日期：2023-08-28

英文摘要：

摘要翻译：

原文链接：

文章：

肿瘤特异性胆碱能CD4+ T淋巴细胞引导肝细胞癌的免疫监测

Tumor-specific cholinergic CD4+ T lymphocytes guide immunosurveillance of hepatocellular carcinoma

原文发布日期：2023-08-28

英文摘要：

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.

摘要翻译：

胆道神经元参与肿瘤进展和扩散。与其它内脏器官相比，在肝脏 parenchyma 中的胆道内迁ination 检测不灵敏。目前尚不清楚是否存在胆道调节肝癌的形式。在这里，我们显示，胆道 T 细胞通过支持抗肿瘤免疫反应抑制肝癌的发展。在小鼠多靶点肝癌模型 (HCC) 中，我们观察到适应性免疫应答的激活和诱导了两个 CD4+ T 细胞群体，它们表达胆碱转氨酰etyl转移酶 (ChAT)，其中包括调控 T 细胞和功能不全 PD-1+ T 细胞。肿瘤抗原驱动这些胆道 T 细胞在肝癌中克隆性扩展。通过基因敲除 Chat，在 T 细胞中观察到非典型细胞增多，肝脏癌因抗肿瘤免疫抑制而恶化。机制上，T 细胞内固有的胆道活性限制了 Ca2+–NFAT 信号通路的激活，这种信号通路由 T 细胞抗原受体激活。在缺乏这种胆道调节的情况下，过活 CD25+ 型调控 T 细胞和功能不全 PD-1+ T 细胞削弱了 HCC 的免疫监视。我们发现，胆道 T 细胞在肝癌免疫学中扮演了一个 previously 未被认识到的角色。