Wang Xin, Lin Weihao, Liu Tiejun, Xu Zhenyi, Wang Zhen, Cao Zheng, Feng Xiaoli, Gao Yibo, He Jie
Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Department of Epidemiology and Biostatistics, School of Public Health, Harbin Medical University, Harbin, China.
Transl Lung Cancer Res. 2021 Dec;10(12):4423-4444. doi: 10.21037/tlcr-21-715.
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.
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.
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.
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.
据报道，细胞焦亡在癌症的肿瘤发生、发展和免疫调节中发挥着关键作用。然而，细胞焦亡在肺腺癌（LUAD）患者肿瘤免疫格局中的潜在作用仍不明确。
在本研究中，我们整理了48个与细胞焦亡相关的基因（PRGs），采用无监督聚类方法确定细胞焦亡模式，并全面评估了500例LUAD患者的细胞焦亡模式和肿瘤免疫格局。使用随机生存森林算法开发了Pyro评分，并进行多变量Cox回归分析以评估Pyro评分的预后价值。
基于48个PRGs的mRNA表达谱，确定了三种具有不同预后、生物学途径和免疫格局的细胞焦亡模式。我们通过上皮间质转化（EMT）、肿瘤内异质性（ITH）程度、总体细胞增殖、新抗原负荷、T细胞受体（TCR）多样性、免疫调节基因表达和患者预后的差异来表征三种细胞焦亡模式。同时，Pyro评分被确立并验证为LUAD的独立预后因素和免疫治疗预测指标。Pyro评分低的患者具有较长的生存时间和增强的免疫浸润特征。在抗癌药物治疗方面，Pyro评分低的患者对靶向致癌相关途径（如DNA损伤修复（DDR）和IGF-1R途径）的药物表现出更高的敏感性，尤其是对抗PD-1/L1免疫治疗的反应增加。
本研究揭示了LUAD中细胞焦亡与肿瘤免疫格局之间的相互作用。对个体LUAD患者细胞焦亡模式的综合评估增强了我们对肿瘤免疫格局的理解，并为LUAD患者的个性化免疫治疗策略提供了新途径。
