1. Academic Validation
  2. NLRP3 inflammasome upregulates PD-L1 expression and contributes to immune suppression in lymphoma

NLRP3 inflammasome upregulates PD-L1 expression and contributes to immune suppression in lymphoma

  • Cancer Lett. 2021 Jan 28;497:178-189. doi: 10.1016/j.canlet.2020.10.024.
Fei Lu 1 Yanan Zhao 1 Yihua Pang 1 Min Ji 1 Yanping Sun 1 Hongchun Wang 2 Jie Zou 3 Yan Wang 4 Guosheng Li 1 Tao Sun 1 Jingxin Li 5 Daoxin Ma 1 Jingjing Ye 6 Chunyan Ji 7
Affiliations

Affiliations

  • 1 Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, PR China.
  • 2 Department of Laboratory Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, PR China.
  • 3 Department of Geriatrics, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, PR China.
  • 4 Department of Hematology, Taian City Central Hospital, Taian, Shandong, 271000, PR China.
  • 5 Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, PR China.
  • 6 Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, PR China. Electronic address: jingjing_ye@163.com.
  • 7 Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, PR China. Electronic address: jichunyan@sdu.edu.cn.
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.

Keywords

Diffuse large B cell lymphoma; Immune checkpoints; Immunosuppression; Interleukin-18; NLRP3.

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