Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Department of Neurosurgery, Ganzhou People's Hospital, Ganzhou, China.
Front Immunol. 2022 Jun 17;13:910490. doi: 10.3389/fimmu.2022.910490. eCollection 2022.
Pyroptosis is a proinflammatory programmed cell death pathway mediated by gasdermins. Exploring the role of pyroptosis can provide new insights into tumor malignancy. The most recent studies on pyroptosis have focused on tumor cells. However, the effects of pyroptosis on the tumor microenvironment (TME), immunotherapeutic responses, and efficacy have been neglected, especially in case of glioma. In this study, four independent glioma cohorts comprising 1,339 samples and a pan-cancer cohort comprising 10,535 tumor samples were analyzed. The relationships among pyroptosis status, prognosis, microenvironment cellular components, and clinical and biological phenotypes were investigated through the identification of pyroptosis subtypes, construction of a gasdermin-related prognostic index (GPI), and evaluation of immunological characteristics in glioma. The Genomics of Drug Sensitivity in Cancer database and "pRRophetic" package in R were used to estimate temozolomide (TMZ) sensitivity. The "Submap" package and external immunotherapy cohorts were used to investigate and confirm the role of GPI in response to and efficacy of immunotherapy in glioma. Finally, potential small-molecule compounds related to GPI were identified using the connectivity map database and mode-of-action analysis. We identified three different pyroptosis subtypes: cluster 1 (C1) characterized by a higher GPI, while cluster 2 (C2) and cluster 3 (C3) characterized by a lower GPI. The high GPI of C1 was associated with glioma progression and worse prognoses, whereas the low GPI of subtype C2 and C3 was associated with better prognoses. However, patients with high GPIs were found to be more sensitive to TMZ and immune checkpoint blockade than those with low GPIs. Furthermore, gasdermin D may be a principal potential biomarker and play key roles in pyroptosis-inducible therapy combined with immunotherapy in glioma. This study provides a clinical, biological, and molecular landscape of pyroptosis and suggests that pyroptosis of glioma cells may perform the dual function of promoting both tumorigenesis and antitumor immunity.
细胞焦亡是由gasdermins 介导的促炎程序性细胞死亡途径。探索细胞焦亡的作用可以为肿瘤恶性程度提供新的见解。最近关于细胞焦亡的研究主要集中在肿瘤细胞上。然而，细胞焦亡对肿瘤微环境（TME）、免疫治疗反应和疗效的影响却被忽视了，尤其是在胶质瘤中。在这项研究中，分析了包含 1339 个样本的四个独立的胶质瘤队列和包含 10535 个肿瘤样本的泛癌队列。通过鉴定细胞焦亡亚型、构建 gasdermin 相关预后指数（GPI）以及评估胶质瘤的免疫特征，研究了细胞焦亡状态、预后、微环境细胞成分与临床和生物学表型之间的关系。利用癌症药物敏感性基因组学数据库和 R 中的“pRRophetic”包来估计替莫唑胺（TMZ）的敏感性。利用“Submap”包和外部免疫治疗队列来研究和证实 GPI 在胶质瘤对免疫治疗的反应和疗效中的作用。最后，使用连接图谱数据库和作用模式分析来鉴定与 GPI 相关的潜在小分子化合物。我们鉴定了三种不同的细胞焦亡亚型：簇 1（C1）的 GPI 较高，而簇 2（C2）和簇 3（C3）的 GPI 较低。C1 的高 GPI 与胶质瘤进展和预后不良有关，而亚型 C2 和 C3 的低 GPI 与较好的预后有关。然而，我们发现高 GPI 患者对 TMZ 和免疫检查点阻断的敏感性高于低 GPI 患者。此外，gasdermin D 可能是一个主要的潜在生物标志物，并在胶质瘤中细胞焦亡诱导治疗联合免疫治疗中发挥关键作用。这项研究提供了细胞焦亡的临床、生物学和分子图谱，并表明胶质瘤细胞的细胞焦亡可能具有促进肿瘤发生和抗肿瘤免疫的双重功能。
