Tumor NLRP3 Amplification Promotes Immunotherapy Resistance by Inhibiting STAT1 Signaling and MHC Class I Expression

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Abstract

Immunotherapy resistance remains a challenge in immuno-oncology and predictive biomarkers are needed to guide combination immunotherapy selection for the individual patient. We show that elevated tumor-intrinsic NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) signaling activity correlates with checkpoint inhibitor resistance in several independent cohorts of stage III/IV melanoma and gastroesophageal (GE) adenocarcinoma patients. In situ hybridization demonstrates that tumor NLRP3 copy-number gain is observed in immunotherapy resistant melanomas and GE adenocarcinomas harboring enhanced NLRP3 signaling activity. Nlrp3 amplification suppresses NOD-, LRR-, and CARD-containing 5 (NLRC5)-mediated MHC class I upregulation, while spatial transcriptomic analysis of patient-derived GE adenocarcinomas confirms that NLRP3 signaling activity inversely correlates with NLRC5 and major histocompatibility (MHC) class I-associated gene expression. Mechanistically, NLRP3 binds to and inhibits signal transducer and activator of transcription 1 (STAT1) dimerization, nuclear translocation, and NLRC5 transcription. Consistent with these findings, pharmacologic inhibition of the NLRP3 inflammasome augments tumor STAT1-NLRC5 signaling, enhances MHC class I surface expression, and overcomes anti-PD-1 resistance in an orthotopic model of gastric adenocarcinoma. This work reveals a fundamental link between cellular stress and tumor-mediated immune evasion and indicates that the tumor NLRP3 signaling pathway merits further clinical study as a therapeutic target and a source of companion biomarkers for overcoming checkpoint inhibitor resistance in cancer patients.

Authors

Balamayroon Theivanthiran, Nagendra Yarla, Kaylee Villarreal, Y-Van Nguyen, Mahere Rezazade Bazaz, Ernesto Pena Calderin, Linda Cao, Kyra Majors, Michael P. Plebanek, Alisha Holtzhausen, Emily Bolch, Douglas B. Johnson, Hope Uronis, John H. Strickler, Nicholas C. DeVito, Brent A. Hanks