NLRP3 inflammasome upregulates PD-L1 expression and contributes to immune suppression in lymphoma. (28th January 2021)

• Record Type: Journal Article
• Authors: Lu, Fei; Zhao, Yanan; Pang, Yihua; Ji, Min; Sun, Yanping; Wang, Hongchun; Zou, Jie; Wang, Yan; Li, Guosheng; Sun, Tao; Li, Jingxin; Ma, Daoxin; Ye, Jingjing; Ji, Chunyan
• Is Part Of: Cancer letters. Volume 497(2021)
• Page Start: 178
• Page End: 189
• Publication Date: 2021-01-28
• Subjects: Diffuse large B cell lymphoma -- NLRP3 -- Interleukin-18 -- Immune checkpoints -- Immunosuppression; Caspase-1 Cysteine-requiring Aspartate Protease-1 -- DLBCL diffuse large B-cell lymphoma -- ELISA enzyme-linked immunosorbent assay -- Foxp3 forkhead box P3 -- ICB Immune checkpoint blockade -- IFN-γ interferon-γ -- IL-1β interleukin-1β -- IL-18 interleukin-18 -- LAG-3 lymphocyte-activation gene 3 -- MDSCs myeloid-derived suppressor cells -- NHL non-Hodgkin lymphoma -- NLRP3 Nod-like receptor pyrin domain 3 -- PD-1 programmed cell death protein 1 -- PD-L1 programmed cell death ligand 1 -- p-STAT3 phosphorylated STAT3 -- STAT signal transducers and activators of transcription -- TAM tumor-associated macrophage -- TIM-3 T cell immunoglobulin domain and mucin domain-3 -- TME tumor microenvironment -- TNF-α tumor necrosis factor-α -- Treg regulatory T cell; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2020.10.024
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: 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. Highlights: NLRP3 inflammasome blockade attenuates lymphoma progression. NLRP3 inflammasome blockade downregulates PD-L1 expression in the TME. NLRP3 inflammasome blockade in vivo reduces the number of immunosuppressive cells. NLRP3 blocker combined with anti-PD-L1 treatment exerts antagonistic effects.