Tang Chaozhi, Ma Jiakang, Liu Xiuli, Liu Zhengchun
Department of Urology, The First Affiliated Hospital of China Medical University, Shenyang, China.
Department of Oncology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Front Oncol. 2020 Oct 5;10:544610. doi: 10.3389/fonc.2020.544610. eCollection 2020.
Molecular classification of bladder cancer is becoming increasingly important for its clinical management. And, the current classifications are primarily based on gene expression profiles. We identified four immunotypes of bladder cancer (referred to as C1-C4) based on gene expression profiles performed by immune-related gene sets in three independent data sets, and proved that this classification is effective and reproducible. We found that C2 is an immune-infiltrating type and C4 is an immune "desert" type. These types are characterized by the up- and downregulation of genes encoding numerous immune checkpoint proteins and HLA and regulating human immune cell subgroups. The survival rate was better for the C2 subtype than for other subtypes. We believe that this can be explained by the antitumor effects of CD4 memory T cells and CD8 T cells as well as their ability to circumvent M0 macrophage antitumor immunity. In addition, C2 was most sensitive to not only anti-PD-1 immunosuppressive therapy, but also conventional chemotherapeutics such as gemcitabine and bleomycin. The C4 subtype was most sensitive to the chemotherapy drugs cisplatin and doxorubicin. This theoretical framework may guide the personalized treatment of bladder cancer in the future. It is worth noting that the C2 immune infiltration type positively correlates with a variety of stromal components, such as enrichment of endothelial cells and fibroblasts, epithelial-mesenchymal transition, and angiogenesis, together with enrichment of seven kinds of stem cells. We further identified tumor-related JAK-STAT and other signaling pathways in the C2 subtype, along with important mutations in the proteins involved in these pathways, revealing the complex mechanism underlying tumor immune escape. Our results, and particularly the identification of hub genes specific to the C2 and C4 subtypes, provide a reference for the development of immunotherapeutic agents against bladder cancer.
膀胱癌的分子分类对其临床管理变得越来越重要。而且，当前的分类主要基于基因表达谱。我们基于在三个独立数据集中由免疫相关基因集进行的基因表达谱，鉴定出了四种膀胱癌免疫类型（称为C1 - C4），并证明这种分类是有效且可重复的。我们发现C2是免疫浸润型，C4是免疫“荒漠”型。这些类型的特征在于编码众多免疫检查点蛋白和HLA以及调节人类免疫细胞亚群的基因的上调和下调。C2亚型的生存率优于其他亚型。我们认为这可以通过CD4记忆T细胞和CD8 T细胞的抗肿瘤作用以及它们规避M0巨噬细胞抗肿瘤免疫的能力来解释。此外，C2不仅对抗PD - 1免疫抑制疗法最敏感，而且对吉西他滨和博来霉素等传统化疗药物也最敏感。C4亚型对化疗药物顺铂和阿霉素最敏感。这个理论框架可能会在未来指导膀胱癌的个性化治疗。值得注意的是，C2免疫浸润型与多种基质成分呈正相关，如内皮细胞和成纤维细胞的富集、上皮 - 间质转化和血管生成，以及七种干细胞的富集。我们进一步在C2亚型中鉴定出肿瘤相关的JAK - STAT和其他信号通路，以及参与这些通路的蛋白质中的重要突变，揭示了肿瘤免疫逃逸的复杂机制。我们的结果，特别是对C2和C4亚型特异性枢纽基因的鉴定，为开发针对膀胱癌的免疫治疗药物提供了参考。
