NLRP3 Promotes Immune Escape by Regulating Immune Checkpoints: A Pan-cancer Analysis
Abstract NLRP3 plays a pathogenic role in tumorigenesis by regulating innate and acquired immunity, apoptosis, differentiation, and intestinal microbes in tumors. In different tumors, NLRP3 plays different roles, and its mechanism is complex. Our research aimed to comprehensively investigated the role of NLRP3 in pan-cancers based on multi-omics data in the TCGA database. We found the expression of NLRP3 was changed in tumors compared with paired non-tumor specimens. Most types of tumors showed increased expression of NLRP3. Among them, the overexpressed NLRP3 in liver hepatocellular carcinoma (LIHC) and ovarian cancer (OV) indicated worse overall survival (OS). Further analysis also confirmed overexpressed NLRP3 in colon cancer (COAD) indicated a high probability of microsatellite instability (MSI) and low tumor mutational burden (TMB), which indicated a better response to immune checkpoint inhibitors (ICIs). We also analyzed the association between NLRP3, immune infiltration, and immune checkpoints. Interestingly, overexpression of NLRP3 was closely related to high infiltration of immune cells (T cells, B cells, etc.) and overexpressed immune checkpoints (PD-1, PD-L1, LAG3, etc.). These results demonstrated NLRP3 promoted immune escape in cancers. Finally, we investigated the expression of various immune checkpoints by treating NLRP3 inhibitor MCC950 during the co-culture of peripheral blood mononuclear cells (PBMC) and LIHC cell line Hep3B. We found MCC950 significantly repressed the expression of PD-L1 and LAG3, and promoted the apoptosis rate of Hep3B. In conclusion, our research comprehensive demonstrated the role of NLRP3 in pan-cancer, especially in LIHC. We confirmed inhibition of NLRP3 promoting the immune killing effect to cancer cells by repressing the expression of immune checkpoints.