NLRP3 signaling drives macrophage-induced adaptive immune suppression in pancreatic carcinoma.
NLRP3 signaling drives macrophage-induced adaptive immune suppression in pancreatic carcinoma.
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DOI：
10.1084/jem.20161707
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发表时间：
2017-06-05
期刊：
影响因子：
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通讯作者：
Miller G
中科院分区：
文献类型：
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作者：
Daley D;Mani VR;Mohan N;Akkad N;Pandian GSDB;Savadkar S;Lee KB;Torres-Hernandez A;Aykut B;Diskin B;Wang W;Farooq MS;Mahmud AI;Werba G;Morales EJ;Lall S;Wadowski BJ;Rubin AG;Berman ME;Narayanan R;Hundeyin M;Miller G
Daley等人表明，巨噬细胞中的NLRP 3信号传导驱动其在胰腺肿瘤微环境中的免疫抑制表型，并增强致耐受性T细胞分化。相反，靶向NLRP 3可防止胰腺癌发生，并与肿瘤内的免疫原性重编程相关。胰腺导管腺癌（PDA）中的肿瘤微环境（TME）以免疫耐受为特征，这使得疾病能够通过适应性免疫而不减弱地进展。然而，这种致耐受性程序的驱动因素并不完全定义。在这项研究中，我们发现NLRP 3促进PDA中免疫抑制性巨噬细胞的扩增。巨噬细胞中的NLRP 3信号传导驱动CD 4 + T细胞分化为肿瘤促进性T辅助2型细胞（Th 2细胞）、Th 17细胞和调节性T细胞群，同时抑制Th 1细胞极化和细胞毒性CD 8 + T细胞活化。NLRP 3信号传导的抑制作用是IL-10依赖性的。药理学抑制或删除NLRP 3、ASC（包含CARD复合物的阿尔茨海默病相关斑点样蛋白）或半胱天冬酶-1可防止PDA，并与TME内先天性和适应性免疫的免疫原性重编程相关。类似地，从NLRP 3 −/−宿主转移携带PDA的巨噬细胞或T细胞具有保护作用。这些数据表明，靶向NLRP 3有望成为PDA的免疫治疗。
Daley et al. show that NLRP3 signaling in macrophages drives their immune-suppressive phenotype in the pancreatic tumor microenvironment and potentiates tolerogenic T cell differentiation. Conversely, targeting NLRP3 protects against pancreatic oncogenesis and is associated with immunogenic reprograming within the tumor. The tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDA) is characterized by immune tolerance, which enables disease to progress unabated by adaptive immunity. However, the drivers of this tolerogenic program are incompletely defined. In this study, we found that NLRP3 promotes expansion of immune-suppressive macrophages in PDA. NLRP3 signaling in macrophages drives the differentiation of CD4+ T cells into tumor-promoting T helper type 2 cell (Th2 cell), Th17 cell, and regulatory T cell populations while suppressing Th1 cell polarization and cytotoxic CD8+ T cell activation. The suppressive effects of NLRP3 signaling were IL-10 dependent. Pharmacological inhibition or deletion of NLRP3, ASC (apoptosis-associated speck-like protein containing a CARD complex), or caspase-1 protected against PDA and was associated with immunogenic reprogramming of innate and adaptive immunity within the TME. Similarly, transfer of PDA-entrained macrophages or T cells from NLRP3−/− hosts was protective. These data suggest that targeting NLRP3 holds the promise for the immunotherapy of PDA.