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

Abstract

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

• hepatocellular carcinoma
• myeloid‐derived suppressor cells
• NLRP3/IL‐1β
• oxaliplatin resistance
• PD‐L1