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).
Keywords: TIGIT; Bladder cancer; Immunotherapy; PD-L1; TMIT; kataegis.