Immunological and Clinical Immunotherapy Implications of NLRP3 Mutations in Melanoma

Background: Recent studies have clearly demonstrated the promotion role of Nod-like receptor protein 3 (NLRP3) inflammasome in melanoma progression. Immune checkpoint inhibitors (ICI) therapy dramatically extended the survival interval of advanced melanoma patients. However, immunologic and immunotherapy implications of mutations of NLRP3 in melanoma were unknown. Methods: We utilized public genomic data of 750 melanoma patients to explore the association of  NLRP3 mutations with immunologic and genomic features. In addition, we curated 336 advanced/metastatic melanoma patients treated with ICI from 6 published studies to analyze response rate and survival outcome in relation to NLRP3 mutations. Findings: Patients with NLRP3 mutations had significantly higher TML ( P < 0.001) and neoantigen load ( P < 0.001). Significantly lower tumor heterogeneity ( P = 0.048) and purity ( P = 0.022) were observed in patients with NLRP3 mutations. NLRP3 mutant patients harbored elevated infiltration of immune-response cells and decreased enrichment of immune-suppressive cells. Immune response signals were also enriched in patients with NLRP3 mutations. Higher response rate ( P = 0.031) and prolonged overall survival ( P = 0.006) were observed in NLRP3 mutated patients in the pooled ICI-treated cohort. Interpretation: NLRP3 mutations were correlated with better immunological characteristics. Patients with NLRP3 mutations had favorable ICI response rate and survival outcome. These results suggest the predictive value of NLRP3 mutations for ICI treatment efficacy in melanoma. Funding: This study was supported by the Shandong Provincial Youth Innovation Team Development Plan of Colleges and Universities [No. 2019-6-156, Lu-Jiao]. Declaration of Interests: The authors declare that there is no conflict of interest regarding the publication of this article.