Yang Wanli, Niu Liaoran, Zhao Xinhui, Duan Lili, Wang Xiaoqian, Li Yiding, Chen Junfeng, Zhou Wei, Zhang Yujie, Fan Daiming, Hong Liu
State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University Xi'an, Shaanxi, China.
Department of Thyroid and Breast Surgery, Xi'an No. 3 Hospital, The Affiliated Hospital of Northwest University, Northwest University Xi'an, Shaanxi, China.
Am J Cancer Res. 2022 Apr 15;12(4):1511-1534. eCollection 2022.
Pyroptosis plays a vital role in the development of cancers; however, its role in regulating immune cell infiltration in tumor microenvironment (TME) and pyroptosis-related molecular subtypes remain unclear. Herein, we comprehensively analyzed the molecular subtypes mediated by the pyroptosis-related genes (PRGs) in gastric cancer (GC). Three pyroptosis patterns were determined with distinct TME cell-infiltrating characteristics and prognosis. Principal component analysis was performed to establish the pyroptosis score. The high pyroptosis score group was featured by increased activated CD4+ T cell infiltration, better prognosis, elevated tumor mutation burden, higher immune and stromal scores, and enhanced response to immunotherapy. However, the low pyroptosis score group was characterized by poorer survival, decreased immune infiltration, and glycerolipid and histidine metabolism pathways. Additionally, high pyroptosis score was confirmed as an independent favorable prognostic factor for overall survival. Three cohorts designed to analyze the response to immunotherapy verified that patients with higher pyroptosis score showed treatment benefit. In summary, our study demonstrated that pyroptosis regulates the complex TME. Assessing the pyroptosis patterns will advance our understanding on TME features and tumor immunology and provide the rationale for designing personalized immunotherapy strategies.
细胞焦亡在癌症发展中起着至关重要的作用；然而，其在调节肿瘤微环境（TME）中免疫细胞浸润以及与细胞焦亡相关的分子亚型方面的作用仍不清楚。在此，我们全面分析了胃癌（GC）中由细胞焦亡相关基因（PRG）介导的分子亚型。确定了三种具有不同TME细胞浸润特征和预后的细胞焦亡模式。进行主成分分析以建立细胞焦亡评分。高细胞焦亡评分组的特征是活化的CD4 + T细胞浸润增加、预后较好、肿瘤突变负担升高、免疫和基质评分更高以及对免疫治疗的反应增强。然而，低细胞焦亡评分组的特征是生存率较差、免疫浸润减少以及甘油脂质和组氨酸代谢途径。此外，高细胞焦亡评分被确认为总生存的独立有利预后因素。三个旨在分析免疫治疗反应的队列证实，细胞焦亡评分较高的患者显示出治疗益处。总之，我们的研究表明细胞焦亡调节复杂的TME。评估细胞焦亡模式将增进我们对TME特征和肿瘤免疫学的理解，并为设计个性化免疫治疗策略提供理论依据。
