Multi-omics Perspective on the Tumor Microenvironment based on PD-L1 and CD8 T-Cell Infiltration in Urothelial Cancer
Multi-omics Perspective on the Tumor Microenvironment based on PD-L1 and CD8 T-Cell Infiltration in Urothelial Cancer
复制标题
基于尿路上皮癌 PD-L1 和 CD8 T 细胞浸润的肿瘤微环境的多组学视角
DOI：
10.7150/jca.28494
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发表时间：
2019-01-01
影响因子：
3.9
通讯作者：
Wang, Xiang
中科院分区：
文献类型：
--
作者：
Chen, Siteng;Zhang, Ning;Wang, Xiang
目的：我们基于膀胱癌患者队列的多维类型数据进行了综合分析，以确定基于程序性细胞死亡1配体（PD-L1）和CD 8 T细胞浸润的肿瘤微环境的多组学观点（基因组学和转录组学）。研究方法：从癌症基因组图谱数据库中检索了408例膀胱癌患者的多维数据类型，包括临床、基因组和转录组数据。根据PD-L1和CD 8A的中位数，将肿瘤样本分为四种肿瘤微环境免疫类型（TMIT）。采用不同的TMIT分析膀胱癌的RNA测序谱、体细胞突变和PD-L1扩增数据。结果：36.8%的膀胱癌患者属于TMIT I型（高PD-L1/高CD 8A）。TIMT亚型与尿路上皮癌的总生存期或无病生存期无显著相关。TMIT I促进CD 8 + T细胞浸润并激活T效应子和干扰素γ（IFN-γ）相关的基因特征。TMIT I组的体细胞突变数、细胞杀伤活性、IFN-γ mRNA表达和TIGIT mRNA表达均显著高于其他TMIT组。我们的研究结果表明，高C>T颠换率和高转换/颠换率（Ti/Tv）在TMIT I膀胱肿瘤。RB 1突变与TMIT I膀胱癌显著相关，并且与TP 53突变显著共现。然而，FGFR 3突变和TP 53突变在TMIT II型膀胱肿瘤中是相互排斥的。更重要的是，在TMIT I和TMIT II膀胱癌之间还发现了FGFR 3/RB 1突变引起的不同氨基酸变化，例如“免疫球蛋白I-set结构域（260-356）“和“蛋白酪氨酸激酶（472-748）"的氨基酸变化。我们还检测到9个基因作为显著的肿瘤相关基因在TMIT I膀胱癌中，其中RAD 51 C已被报道在DNA损伤反应中起重要作用。进一步的分子机制分析发现，TMIT I与抗肿瘤免疫相关信号通路密切相关，并且在TMIT I膀胱肿瘤的21号染色体上存在kataegis。结论：基于PD-L1表达和CD 8 + CTL状态将膀胱癌分为四种TMIT是膀胱肿瘤免疫治疗的适当方法。TMIT I（高PD-L1/高CD 8A）与更多的体细胞突变负荷显著相关，并促进CD 8 + T细胞浸润，激活T效应子和IFN-γ相关基因特征。TMIT I和TMIT II之间体细胞变异的改变景观不同（低PD-L1/低CD 8A）。
Objectives: We carried out an integrated analysis based on multiple-dimensional types of data from cohorts of bladder cancer patients to identify multi-omics perspective (genomics and transcriptomics) on the tumor microenvironment on the bases of the programmed cell death 1 ligand (PD-L1) and CD8 T-cell infiltration in urothelial carcinoma. Methods: Multiple-dimensional types of data, including clinical, genomic and transcriptomic data of 408 bladder cancer patients were retrieved from the Cancer Genome Atlas database. Based on the median values of PD-L1 and CD8A, the tumor samples were grouped into four tumor microenvironment immune types (TMIT). The RNA sequencing profiles, somatic mutation and PD-L1 amplification data of bladder cancer were analyzed by different TMITs. Results: Our research demonstrated that 36.8% of the evaluated bladder cancer belonged to TMIT I (high PD-L1/high CD8A). TIMT subtypes were not significantly associated with overall survival or disease free survival in urothelial cancer. TMIT I facilitates CD8+ T-cell infiltration and activates T-effector and interferon gamma (IFN-γ) associated gene signature. The number of somatic mutations, cytolytic activity, IFN-γ mRNA expression and TIGIT mRNA expression in TMIT I was remarkably higher than those in other TMIT groups. Our results showed a high rate of C>T transversion and a high rate of transition/transversion (Ti/Tv) in TMIT I bladder tumors. The RB1 mutation was significantly associated with TMIT I bladder cancer and be significantly co-occurring with the TP53 mutation. However, FGFR3 mutation and TP53 mutation were mutually exclusive in TMIT II bladder tumors. More importantly, different amino acid changes by FGFR3/RB1 mutations were also found between TMIT I and TMIT II bladder cancer, such as amino acid changes in “Immunoglobulin I-set domain (260-356)”and “Protein tyrosine kinase (472-748)”. We also detected 9 genes as significantly cancer-associated genes in TMIT I bladder cancer, of which, RAD51C has been reported to play an important role in DNA damage responses. Further analysis concentrated on the potential molecular mechanism found that TMIT I was significantly associated with anti-tumor immune-related signaling pathway, and kataegis was present on chromosome 21 in TMIT I bladder tumors. Conclusions: The classification of bladder cancer into four TMITs on the bases of the PD-L1 expression and the CD8+ CTLs statuses is an appropriate approach for bladder tumor immunotherapy. TMIT I (high PD-L1/high CD8A) is significantly correlated with more somatic mutation burden, and facilitates CD8+ T-cell infiltration and activates T-effector and IFN-γ associated gene signature. Alteration landscape for somatic variants was different between TMIT I and TMIT II (low PD-L1/low CD8A).