Abstract
Immunotherapy resistance remains a major challenge in immuno-oncology. We have previously demonstrated that a tumor-intrinsic NLRP3 inflammasome signaling pathway promotes adaptive immunotherapy resistance by inducing the recruitment of granulocytic myeloid-derived suppressor cells. We now confirm that elevated tumor NLRP3 signaling activity correlates with checkpoint inhibitor resistance in several independent cohorts of stage III and IV melanoma patients, as well as in advanced gastroesophageal (GE) adenocarcinoma patients. In situ hybridization studies further demonstrate that tumor NLRP3 copy-number gain is observed in immunotherapy resistant melanomas and GE adenocarcinomas harboring enhanced NLRP3 signaling activity. Spatial transcriptomic analysis of GE adenocarcinoma tissues reveals that NLRP3 signaling activity inversely correlates with NLRC5 and MHC class I-associated gene expression. Indeed, pre-clinical models of melanoma and GE adenocarcinoma demonstrate that Nlrp3 amplification suppresses NLRC5-mediated MHC class I upregulation, while pharmacologic NLRP3 inhibition augments tumor MHC class I surface levels. Upon activation, tandem mass spectrometry-supported signaling studies reveal that NLRP3 binds to and inhibits STAT1 dimerization, nuclear translocation, and NLRC5 transcription. Consistent with these findings, inhibiting the NLRP3 inflammasome augments tumor STAT1-NLRC5 signaling and overcomes anti-PD-1 resistance in an orthotopic model of chromosomal instability (CIN) gastric adenocarcinoma. This work indicates that the tumor NLRP3 inflammasome signaling pathway merits further clinical study as a therapeutic target and a source of companion biomarkers for overcoming checkpoint inhibitor resistance in cancer patients.