Crosstalk of necroptosis and pyroptosis defines tumor microenvironment characterization and predicts prognosis in clear cell renal carcinoma.
Crosstalk of necroptosis and pyroptosis defines tumor microenvironment characterization and predicts prognosis in clear cell renal carcinoma.
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坏死性凋亡和焦亡的串扰定义了透明细胞肾癌的肿瘤微环境特征并预测预后
DOI：
10.3389/fimmu.2022.1021935
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发表时间：
2022
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
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细胞凋亡和坏死凋亡是最近发现的两种肿瘤微环境（TME）中免疫原性细胞死亡的形式，表明在肿瘤转移中的重要参与。然而，在ccRCC患者中定义肿瘤微环境和预后的坏死性凋亡和焦亡的特征仍然未知。我们系统地研究了死亡和焦亡相关基因（NPRGs）的转录变异和表达模式。在筛选出坏死-焦亡簇后，通过GSVA富集分析探索簇的潜在功能注释。采用NPG评分法建立预后模型并进行验证。然后，还分别探讨NPG评分与临床特征、癌症干细胞（CSC）指数、肿瘤突变负荷（TMB）、TME和免疫检查点基因（ICGs）的相关性，以评估ccRCC的预后预测价值。微阵列筛选确定了27个上调和1个下调的NPRG。筛选了10个总生存期相关的NPRG，以构建NPG预后模型，该模型表明具有较低NPG评分的ccRCC患者具有更好的预后特征（P< 0.001），这使用外部队列进行了验证。单因素和多因素分析沿着Kaplan-Meier生存分析表明，NPG评分预后模型可以作为一个独立的预后因素，1- 5年总生存期的诺模图AUC值在校准图中具有良好的一致性，表明所提出的预后特征在ccRCC中具有良好的预测能力。根据富集的GO、KEGG和GSEA分析，高-/sNPG评分被证明与肿瘤生长和免疫相关的生物学过程有关。将具有高NPG评分的患者与具有低NPG评分的患者进行比较，揭示了在临床特征、恶性肿瘤的生长和复发（CSC指数）、TME细胞浸润和免疫应答方面的显著差异（P< 0.005），这可能使NPG评分在临床治疗环境中具有多功能性。此外，还发现AIM 2、CASP 4、GSDMB、NOD 2和RBCK 1在ccRCC细胞系和肿瘤组织中高度表达，并且GASP 4和GSDMB促进ccRCC细胞的增殖、迁移和侵袭。这项研究首次表明，针对TME表征的NPG评分特征可能为其在ccRCC预后预测中的临床应用提供新的见解。
Pyroptosis and necroptosis are two recently identified forms of immunogenic cell death in the tumor microenvironment (TME), indicating a crucial involvement in tumor metastasis. However, the characteristics of necroptosis and pyroptosis that define tumor microenvironment and prognosis in ccRCC patients remain unknown. We systematically investigated the transcriptional variation and expression patterns of Necroptosis and Pyroptosis related genes (NPRGs). After screening the necroptosis-pyroptosis clusters, the potential functional annotation for clusters was explored by GSVA enrichment analysis. The Necroptosis-Pyroptosis Genes (NPG) scores were used for the prognosis model construction and validation. Then, the correlations of NPG score with clinical features, cancer stem cell (CSC) index, tumor mutation burden (TMB), TME, and Immune Checkpoint Genes (ICGs) were also individually explored to evaluate the prognosis predictive values in ccRCC. Microarray screenings identified 27 upregulated and 1 downregulated NPRGs. Ten overall survival associated NPRGs were filtered to construct the NPG prognostic model indicating a better prognostic signature for ccRCC patients with lower NPG scores (P< 0.001), which was verified using the external cohort. Univariate and multivariate analyses along with Kaplan-Meier survival analysis demonstrated that NPG score prognostic model could be applied as an independent prognostic factor, and AUC values of nomogram from 1- to 5- year overall survival with good agreement in calibration plots suggested that the proposed prognostic signature possessed good predictive capabilities in ccRCC. A high-/sNPG score is proven to be connected with tumor growth and immune-related biological processes, according to enriched GO, KEGG, and GSEA analyses. Comparing patients with a high-NPG score to those with a low-NPG score revealed significant differences in clinical characteristics, growth and recurrence of malignancies (CSC index), TME cell infiltration, and immunotherapeutic response (P< 0.005), potentially making the NPG score multifunctional in the clinical therapeutic setting. Furthermore, AIM2, CASP4, GSDMB, NOD2, and RBCK1 were also found to be highly expressed in ccRCC cell lines and tumor tissues, and GASP4 and GSDMB promote ccRCC cells’ proliferation, migration, and invasion. This study firstly suggests that targeting the NPG score feature for TME characterization may lend novel insights into its clinical applications in the prognostic prediction of ccRCC.