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NLRP3 inflammasome upregulates PD-L1 expression and contributes to immune suppression in lymphoma
Cancer Letters ( IF 9.1 ) Pub Date : 2020-10-19 , DOI: 10.1016/j.canlet.2020.10.024
Fei Lu , Yanan Zhao , Yihua Pang , Min Ji , Yanping Sun , Hongchun Wang , Jie Zou , Yan Wang , Guosheng Li , Tao Sun , Jingxin Li , Daoxin Ma , Jingjing Ye , Chunyan Ji

The NLRP3 inflammasome plays a pro-tumorigenic role in various malignancies. However, its potential role in lymphomagenesis remains unclear. In this study, we identified an immunosuppressive state in patients with diffuse large B cell lymphoma (DLBCL), which was characterized by markedly elevated interleukin (IL)-18 levels in lymphoma tissues and positive correlation with programmed death ligand 1 (PD-L1) expression. Furthermore, NLRP3 inflammasome activation in DLBCL cell lines upregulated PD-L1 and reduced the proportion of cytotoxic T cells. NLRP3 inflammasome blockade in vivo suppressed lymphoma growth and ameliorated anti-tumor immunity by downregulating PD-L1 in the tumor microenvironment and decreasing the proportion of PD-1/TIM-3-expressing T cells, myeloid-derived suppressor cells, tumor-associated macrophages, and regulatory T cells. Further in vivo studies revealed IL-18 as the main effector cytokine involved in the negative regulation of anti-lymphoma immunity. Interestingly, NLRP3 blockers combined with anti-PD-L1 treatment exerted antagonistic effects during lymphoma therapy. Altogether, our findings indicate that NLRP3 inflammasome promotes immunosuppression by modulating PD-L1 and immune cells. Accordingly, this study highlights the prognostic and therapeutic values of the NLRP3 inflammasome in lymphoma.



中文翻译:

NLRP3炎性小体上调PD-L1表达并有助于淋巴瘤的免疫抑制

NLRP3炎性小体在各种恶性肿瘤中起促肿瘤作用。然而,其在淋巴瘤发生中的潜在作用仍不清楚。在这项研究中,我们确定了弥漫性大B细胞淋巴瘤(DLBCL)患者的免疫抑制状态,其特征是淋巴瘤组织中白介素(IL)-18水平显着升高,并与程序性死亡配体1(PD-L1)正相关表达。此外,DLBCL细胞系中的NLRP3炎性体激活上调了PD-L1并降低了细胞毒性T细胞的比例。体内NLRP3炎性体阻断通过下调肿瘤微环境中的PD-L1并减少表达PD-1 / TIM-3的T细胞,髓样来源的抑制细胞,肿瘤相关巨噬细胞和调节性T细胞的比例来抑制淋巴瘤生长并改善抗肿瘤免疫力。进一步的体内研究表明,IL-18是参与抗淋巴瘤免疫力负调节的主要效应细胞因子。有趣的是,NLRP3阻滞剂联合抗PD-L1治疗在淋巴瘤治疗期间发挥了拮抗作用。总之,我们的发现表明NLRP3炎性小体通过调节PD-L1和免疫细胞来促进免疫抑制。因此,本研究强调了NLRP3炎性小体在淋巴瘤中的预后和治疗价值。

更新日期:2020-10-30
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