Cross-talk of pyroptosis and tumor immune landscape in lung adenocarcinoma

Background: Pyroptosis has been reported to exhibit a crucial effect on tumorigenesis, development and immune regulation in cancers. However, the potential roles of pyroptosis in the tumor immune landscape remain elusive in lung adenocarcinoma (LUAD) patients. Methods: In this study, we curated 48 pyroptosis related genes (PRGs), used an unsupervised clustering method to determine pyroptosis patterns and comprehensively evaluated the pyroptosis patterns and tumor immune landscape of 500 LUAD patients. The Pyro score was developed using random survival forest algorithm, and multivariate Cox regression analysis was performed to evaluate the prognostic value of the Pyro score. Results: Based on the mRNA expression profiles of 48 PRGs, three pyroptosis patterns were identified with distinct prognosis, biological pathways and immune landscape. We characterized three pyroptosis patterns by differences in epithelial mesenchymal transition (EMT), extent of intratumor heterogeneity (ITH), overall cell proliferation, neoantigen load, T-cell receptor (TCR) diversity, expression of immunomodulatory genes, and patient prognosis. Meanwhile, the Pyro score was established and validated as an independent prognostic factor and immunotherapy predictor for LUAD. Patients with low Pyro score were characterized by prolonged survival time, enhanced immune infiltration. In response to anti-cancer drugs, patients with low Pyro score exhibited higher sensitivities of drugs which targeted oncogenic related pathways, such as DNA damage repair (DDR) and IGF-1R pathways, and especially increased response to anti-PD-1/L1 immunotherapy. Conclusions: This study revealed the cross-talk between pyroptosis and the tumor immune landscape in LUAD. The comprehensive evaluation of pyroptosis patterns in individual LUAD patients enhances our understanding of the tumor immune landscape and provides a new way toward personalized immunotherapeutic strategies for LUAD patients.