Abstract 4147: Activated pyroptosis prior to treatment marks a potential response to immunotherapy in cancers

Abstract Purpose: Immune checkpoint inhibitors (ICIs) have achieved remarkable survival improvement in multiple cancers by exerting anti-tumor effects through augmenting adaptive immunity. However, 60%-70% of patients showed primary resistance to ICIs, and the underlying mechanisms remained unclear. Pyroptosis is a programmed cell death accompanied by a robust inflammatory response with the secretion of pro-inflammatory molecules, and thus it has the potential to be a promising biomarker for immunotherapy. Methods: A dataset with the clinical and transcriptomic profiles was derived from 16 randomized controlled trials and studies on ICIs treatment in multiple solid tumors, including melanoma, urothelial cancer, non-small cell lung cancer, renal cell cancer, breast cancer, and esophageal cancer. The responder was defined as patients achieving complete or partial response, while the non-responder was defined as patients with stable or progressive disease. According to previous studies, we generated a cytotoxic pyroptosis-related gene set, including CASP1, CASP3, CASP4, CASP5, CASP8, GSDMB, GSMDC, GSDMD, GSDME, GZMA, GZMB, to explore the association of cytotoxic pyroptosis with response to ICIs. In addition, the previously defined gene set from the Gene Ontology working group that contains a pyroptosis-related gene set was also included to represent the level of total pyroptosis. Single sample Gene Set Enrichment Analysis (ssGSEA) was performed, and the fold-changes and p-values of gene sets were merged with the R package “MetaVolcanoR”. Patients in each subset were split by the median of the ssGSEA score of pyroptosis-related genes and identified as with relatively activated and inhibited pyroptosis, respectively. A P-value < 0.05 was considered significant. Results: A total of 1,407 patients were analyzed, including 475 responders and 932 non-responders. The ssGSEA revealed that both the pyroptosis and the cytotoxic pyroptosis gene sets were enriched in responders, while the cytotoxic pyroptosis-related gene set was one of the top five ones among the 545 enriched in responders. Moreover, the survival analysis showed that in urothelial and non-small cell lung cancer, patients with activated pyroptosis prior to treatment had better progression-free survival and overall survival after ICIs therapies. These results suggested that an activated status of pyroptosis, especially the pyroptotic process related to cytotoxic events, is a marker for better response to ICIs. Conclusions: The transcriptomic analysis of universal immunotherapy biomarkers identifies an pre-existing activated status of pyroptosis within the tumor microenvironment was associated with a better ICIs response across different cancer types, and thus these pyroptosis-related genes may serve as valuable immunotherapy markers and in silico fundamental tool for exploring pyroptosis in tumor immunity. Citation Format: Yumo Xie, Xiaolin Wang, Meijin Huang, Yanxin Luo, Huichuan Yu. Activated pyroptosis prior to treatment marks a potential response to immunotherapy in cancers. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4147.