The ion channel TRPV1 gain-of-function reprograms the immune microenvironment to facilitate colorectal tumorigenesis
The ion channel TRPV1 gain-of-function reprograms the immune microenvironment to facilitate colorectal tumorigenesis
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DOI：
10.1016/j.canlet.2021.12.012
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发表时间：
2022-02-28
期刊：
影响因子：
9.7
通讯作者：
Dai, Yun
中科院分区：
文献类型：
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作者：
Jiang, Xuehui;Wang, Chaohui;Dai, Yun
瞬时受体电位香草酸1（TRPV 1）是一种Ca 2+渗透性离子通道，作为细胞传感器，并参与肿瘤微环境串扰。然而，TRPV 1在结直肠癌（CRC）中的功能作用仍然存在争议。通过使用TRPV 1功能获得模型，我们以前报道过功能亢进的TRPV 1通过调节粘膜免疫加重实验性结肠炎。在这里，我们发现TRPV 1功能获得性显著促进结肠炎相关癌症的肿瘤发生和进展，肿瘤数量和大小的增加证明了这一点。系统性TRPV 1超活化通过改变巨噬细胞活化状态和将Th 1/Th 2平衡向Th 2表型转移来促进肿瘤容许微环境。从机制上讲，TRPV 1功能获得直接增强巨噬细胞中M1细胞因子的产生，并通过促进钙调神经磷酸酶/活化T细胞核因子（NFATc 2）信号传导激活来增强Th 2免疫反应。在CRC患者中，TRPV 1在肿瘤免疫浸润细胞中表达增加。TRPV 1水平与CRC进展相关，并可能影响临床结局。我们的研究揭示了TRPV 1在调节结直肠肿瘤发生过程中的免疫微环境中的重要作用。TRPV 1可能是CRC免疫治疗的潜在靶点。
Transient receptor potential vanilloid 1 (TRPV1) is a Ca2+-permeable ion channel that acts as cellular sensor and is implicated in the tumor microenvironment cross talk. However, the functional role of TRPV1 in colorectal cancer (CRC) is still controversial. By using a TRPV1 gain-of-function model, we previously reported that hyperfunctional TRPV1 exacerbated experimental colitis by modulating mucosal immunity. Here, we found that TRPV1 gain-of-function significantly promoted tumor initiation and progression in colitis-associated cancer, as evidenced by the increase in the number and size of tumor. Systemic TRPV1 hyperactivation fostered a tumor permissive microenvironment through altering macrophage activation status and shifting the Th1/Th2 balance towards Th2 phenotype. Mechanistically, TRPV1 gain-of-function directly potentiated M1 cytokine production in macrophage and enhanced Th2 immune response by promoting Calcineurin/nuclear factor of activated T cells (NFATc2) signaling activation. In patients with CRC, TRPV1 expression was increased in tumor immune infiltrating cells. TRPV1 level was associated with CRC progression and could impact clinical outcome. Our study reveals an important role for TRPV1 in regulating the immune microenvironment during colorectal tumorigenesis. TRPV1 might be a potential target for CRC immunotherapy.