Zhang Yan, Chen Xianwu, Fu Qinghe, Wang Feifan, Zhou Xuejian, Xiang Jiayong, He Ning, Hu Zhenghui, Jin Xiaodong
Department of Urology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, Zhejiang, People's Republic of China.
Cancer Cell Int. 2021 Dec 14;21(1):667. doi: 10.1186/s12935-021-02384-y.
Increasing evidence has indicated that pyroptosis could regulate the tumor immune microenvironment (TIME) to affect the tumor development. As a highly immunogenic tumor, clear cell renal cell carcinoma (ccRCC) can benefit from immunotherapy, but related research on pyroptosis in the TIME of ccRCC is still deficient.
Available data derived from TCGA and GEO databases were analyzed to identify the different expression profiles of pyroptosis in ccRCC and normal tissues, and the correlation of pyroptosis regulators with TIME was evaluated in ccRCC.
According to consensus clustering analysis, two differential expression levels of subtypes were identified to affect patient prognosis, and were related to histological tumor stage and grade. Immune cells were calculated by the CIBERSORT algorithm. Higher infiltrated levels of B cells naive, T cells CD4 memory resting, NK cells resting, monocytes, macrophages were observed in Cluster 1, while higher infiltrated levels of CD8 T cells, T follicular helper cells, and Tregs were observed in Cluster 2. Gene set enrichment analysis indicated that Cluster 2 was enriched in multiple immune-related pathways, including the JAK-STAT signaling pathway. Moreover, overexpression of eight immune checkpoints was related to ccRCC development, especially in Cluster 2. As four potentially key pyroptosis regulators, AIM2, CASP5, NOD2, and GZMB were confirmed to be upregulated in ccRCC by RT-qPCR analysis and further verified by the HPA database. Further pan-cancer analysis suggested that these four pyroptosis regulators were differentially expressed and related to the TIME in multiple cancers.
The present study provided a comprehensive view of pyroptosis regulators in the TIME of ccRCC, which may provide potential value for immunotherapy.
越来越多的证据表明，细胞焦亡可调节肿瘤免疫微环境（TIME）以影响肿瘤发展。作为一种具有高度免疫原性的肿瘤，透明细胞肾细胞癌（ccRCC）可从免疫治疗中获益，但关于ccRCC的TIME中细胞焦亡的相关研究仍然不足。
分析来自TCGA和GEO数据库的可用数据，以确定ccRCC和正常组织中细胞焦亡的不同表达谱，并评估ccRCC中细胞焦亡调节因子与TIME的相关性。
根据一致性聚类分析，确定了两种影响患者预后的亚型差异表达水平，且与组织学肿瘤分期和分级相关。通过CIBERSORT算法计算免疫细胞。在簇1中观察到幼稚B细胞、静止的CD4记忆T细胞、静止的NK细胞、单核细胞、巨噬细胞的浸润水平较高，而在簇2中观察到CD8 T细胞、滤泡辅助性T细胞和调节性T细胞的浸润水平较高。基因集富集分析表明，簇2在多个免疫相关途径中富集，包括JAK-STAT信号通路。此外，8种免疫检查点的过表达与ccRCC发展相关，尤其是在簇2中。作为4种潜在的关键细胞焦亡调节因子，通过RT-qPCR分析证实AIM2、CASP5、NOD2和GZMB在ccRCC中上调，并通过HPA数据库进一步验证。进一步的泛癌分析表明，这4种细胞焦亡调节因子在多种癌症中差异表达并与TIME相关。
本研究全面阐述了ccRCC的TIME中的细胞焦亡调节因子，可能为免疫治疗提供潜在价值。
