NLRP3/IL-1β induced myeloid-derived suppressor cells recruitment and PD-L1 upregulation promotes oxaliplatin resistance of hepatocellular carcinoma

Wenfeng Liu; Feng Zhang; Bing Quan; Fan Yao; Rongxin Chen; Zhenggang Ren; Xin Yin

doi:10.1002/mco2.447

NLRP3/IL-1β induced myeloid-derived suppressor cells recruitment and PD-L1 upregulation promotes oxaliplatin resistance of hepatocellular carcinoma

MedComm (2020). 2023 Dec 19;4(6):e447. doi: 10.1002/mco2.447. eCollection 2023 Dec.

Authors

Wenfeng Liu^{1

2}, Feng Zhang^{1

2}, Bing Quan^{1

2}, Fan Yao^{1

2}, Rongxin Chen^{1

2}, Zhenggang Ren^{1

2}, Xin Yin^{1

2}

Affiliations

¹ Department of Hepatic Oncology, Liver Cancer Institute, Zhongshan Hospital Fudan University Shanghai China.
² Department of National Clinical Research Center for Interventional Medicine Zhongshan hospital, Fudan university Shanghai China.

Abstract

Oxaliplatin is commonly used as the first-line chemotherapeutic agent for advanced hepatocellular carcinoma (HCC). Unfortunately, the acquired resistance, limits the effectiveness of oxaliplatin and the underlying mechanisms remain unknown. Therefore, we explored the role of NOD-like receptor protein 3 (NLRP3)/IL-1β in mediating oxaliplatin resistance in HCC. We observed that NLRP3/IL-1β expression was much higher in oxaliplatin-resistant HCC cells. To further understand its impact on drug resistance, we knocked down NLRP3 and observed that it sensitized HCC cells to the growth-inhibitory effects of oxaliplatin and induced cell apoptosis. NLRP3/IL-1β overexpressing tumor cells also attracted polymorphonuclear myeloid-derived suppressor cells. Using mouse models, we demonstrated that NLRP3/IL-1β inhibition by short hairpin RNA or MCC950 effectively overcame oxaliplatin resistance. Furthermore, NLRP3/IL-1β inhibition resulted in reduced expression of PD-L1. We also found that PD-L1 antibody combined with NLRP3/IL-1β blockade displayed significant antitumor effect in HCC. Overall, our study provides compelling evidence supporting the essential role of NLRP3/IL-1β in conferring resistance to oxaliplatin and reshaping the immunosuppressive microenvironment in HCC. Targeting NLRP3/IL-1β presents a potential therapeutic target for overcoming oxaliplatin resistance and reshaping microenvironment of HCC.

Keywords: NLRP3/IL‐1β; PD‐L1; hepatocellular carcinoma; myeloid‐derived suppressor cells; oxaliplatin resistance.