Perineural Invasion Reprograms the Immune Microenvironment through Cholinergic Signaling in Pancreatic Ductal Adenocarcinoma
Perineural Invasion Reprograms the Immune Microenvironment through Cholinergic Signaling in Pancreatic Ductal Adenocarcinoma
复制标题
神经周围侵袭通过胆碱能信号重新编程胰腺导管腺癌的免疫微环境
DOI：
10.1158/0008-5472.can-19-2689
复制
发表时间：
2020-05-15
期刊：
影响因子：
11.2
通讯作者：
Sun, Yong-Wei
中科院分区：
文献类型：
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作者：
Yang, Min-Wei;Tao, Ling-Ye;Sun, Yong-Wei
这些发现为调节有严重神经侵袭的胰腺导管腺癌的免疫抑制微环境提供了一种有希望的治疗策略。神经侵犯是胰腺导管腺癌(PDAC)的共同特征。在这里，我们研究了神经侵袭对微环境的影响以及这是如何影响PDAC进展的。比较不同神经侵袭状态的PDAC组织的转录组表达谱，并检测肿瘤内T细胞密度和神经递质水平。神经侵袭与免疫反应受损有关，表现为CD8+T细胞和Th1细胞减少，Th2细胞增加。在严重神经侵袭时，乙酰胆碱水平升高。乙酰胆碱通过HDAC1介导的CCL5抑制，削弱了PDAC细胞招募CD8+T细胞的能力。此外，乙酰胆碱以剂量依赖的方式直接抑制CD8+T细胞产生干扰素γ，并且有利于Th2而不是Th1分化。此外，在原位PDAC模型中，胆碱能信号的过度激活通过抑制瘤内T细胞反应来促进肿瘤生长。相反，通过双侧膈下迷走神经切断术阻断荷瘤小鼠的神经侵袭与CD8+T细胞的增加、Th1/Th2比率的升高和生存的改善有关。总而言之，神经侵袭触发的胆碱能信号通过促进免疫抑制微环境促进肿瘤生长，其特征是CD8+T细胞浸润受损和Th1/Th2比率降低。意义：这些发现为调节有严重神经侵袭的胰腺导管腺癌的免疫抑制微环境提供了一个有前景的治疗策略。
These findings provide a promising therapeutic strategy to modulate the immunosuppressive microenvironment of pancreatic ductal adenocarcinoma with severe perineural invasion. Perineural invasion is a common feature of pancreatic ductal adenocarcinoma (PDAC). Here, we investigated the effect of perineural invasion on the microenvironment and how this affects PDAC progression. Transcriptome expression profiles of PDAC tissues with different perineural invasion status were compared, and the intratumoral T-cell density and levels of neurotransmitters in these tissues were assessed. Perineural invasion was associated with impaired immune responses characterized by decreased CD8+ T and Th1 cells, and increased Th2 cells. Acetylcholine levels were elevated in severe perineural invasion. Acetylcholine impaired the ability of PDAC cells to recruit CD8+ T cells via HDAC1-mediated suppression of CCL5. Moreover, acetylcholine directly inhibited IFNγ production by CD8+ T cells in a dose-dependent manner and favored Th2 over Th1 differentiation. Furthermore, hyperactivation of cholinergic signaling enhanced tumor growth by suppressing the intratumoral T-cell response in an orthotopic PDAC model. Conversely, blocking perineural invasion with bilateral subdiaphragmatic vagotomy in tumor-bearing mice was associated with an increase in CD8+ T cells, an elevated Th1/Th2 ratio, and improved survival. In conclusion, perineural invasion–triggered cholinergic signaling favors tumor growth by promoting an immune-suppressive microenvironment characterized by impaired CD8+ T-cell infiltration and a reduced Th1/Th2 ratio. Significance: These findings provide a promising therapeutic strategy to modulate the immunosuppressive microenvironment of pancreatic ductal adenocarcinoma with severe perineural invasion.