Activation of the DDR Pathway Leads to the Down-Regulation of the TGFβ Pathway and a Better Response to ICIs in Patients With Metastatic Urothelial Carcinoma

Abstract

Immune checkpoint inhibitors (ICIs) have changed the treatment paradigm of metastatic urothelial carcinoma (mUC), a dominant type of bladder cancer (BC). Previous studies have shown an association between gene mutations in the DNA damage response (DDR) pathway and the immunotherapy response in mUC but have neglected the effect of the activation level of the DDR pathway on the ICI response in mUC. A published immunotherapy cohort with genome, transcriptome and survival data for 348 mUC patients was used. An external cohort (The Cancer Genome Atlas Bladder Cancer) and the GSE78220 cohort were used for validation. The activation level of the DDR pathway was quantified using single-sample gene set enrichment analysis (ssGSEA). Further analysis on the genome, immunogenicity, and the immune microenvironment was conducted using the DDR ssGSEA enrichment score-high (DSSH) group and the DDR ssGSEA enrichment score-low (DSSL) group. In the mUC cohorts, the DSSH group was associated with longer overall survival times (P=0.026; Hazard ratio=0.67; 95%CI: 0.46−0.95). The DSSH group was also associated with higher tumor mutation burden, neoantigen load, immune-activated cell patterns, and immune-related gene expression levels. The GSEA results indicated an immune activation state in DSSH group, which correlated with a down-regulation in the transforming growth factor β receptor signaling pathway. Our study suggests that the activation level of the DDR pathway may be a novel predictive marker for immunotherapy efficacy in patients with mUC.

Comprehensive Analyses Identify APOBEC3A as a Genomic Instability-Associated Immune Prognostic Biomarker in Ovarian Cancer

“…More importantly, PLCH1 was also found to be exclusively mutated with TP53, which illustrated that PLCH1 might have similar functions with TP53 in the same pathway. Additionally, the DDR pathway is acknowledged to maintain the genome stability when DNA damage occurs, which has been found to have a close correlation with response to ICB therapy (71)(72)(73). Also, APOBEC3A expression was reported to cause DNA damage responses of cancers (74,75).…”

Comprehensive Analysis of the Immune Microenvironment in Checkpoint Inhibitor Pneumonitis

“…Enrichment analysis, or more specifically the enrichGO function in the ClusterProfiler R package, was used to evaluate the fold enrichment score and p-value of differential genes in the GP-BP, GO-CC, GO-MF and KEGG pathways. In addition, the ssGSEA algorithm ( 19 ) was used to evaluate the performance of each patient based on their GO-BP, GO-CC, GO-MF, KEGG, and REACTOME pathway data. The gene set of the ssGSEA enrichment analysis was derived from hallmark gene sets, curved gene sets (C2), and ontology gene sets (C5) in the molecular signatures database (MsigDB) ( 20 ).…”

TNF-Alpha Pathway Alternation Predicts Survival of Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer

“…For example, chemokines such as CXCL10 and CXCL9 can enhance immune infiltration and antitumor immunity by recruiting CD8+ T cells, dendritic cells (DCs) and natural killer (NK) cells ( 62 ). IFNγ can support the proliferation and differentiation of CD8+ T cells ( 63 , 64 ). Dong et al.…”