Fig. 6: KDM5B and FGFR3 are potential therapeutic targets to activate an immune response in S1 CPI-MIBCs. | Nature Communications

Fig. 6: KDM5B and FGFR3 are potential therapeutic targets to activate an immune response in S1 CPI-MIBCs.

From: Expression-based subtypes define pathologic response to neoadjuvant immune-checkpoint inhibitors in muscle-invasive bladder cancer

Fig. 6

a KDM5B regulon target genes (red = positive targets, blue = negative targets), with immune-related genes marked by black discs. b Validating the negative association between KDM5B regulon activity and ESTIMATE ImmuneScore. (i) The relationship of KDM5B regulon activity to ESTIMATE ImmuneScore in the PURE01 pre-treatment cohort, with samples (dots) colored by KDM5B regulon activity status. (ii) Rank-sorted profile of KDM5B regulon activity across the PURE01 pre-treatment cohort, showing activated (n = 23, 28%), undefined (n = 23, 28%), and repressed (n = 36, 43%) cohort subsets. (iii) Relationship of KDM5B regulon activity to ESTIMATE ImmuneScore in the TCGA-BLCA cohort (n = 404). (iv) Rank-sorted profile of KDM5B regulon activity across the TCGA-BLCA cohort, showing activated (n = 111, 27%), undefined (n = 146, 36%), and repressed (n = 147, 36%) cohort subsets. c Left: Unsupervised clustering of single-cell RNA sequencing data from three human MIBC tumors identified 19 clusters consisting of cells from the tumor, immune, and stromal compartments. Right: (i) Unsupervised reclustering of scRNA-Seq data for epithelial cells identified nine sub-clusters. (ii) Distribution of a luminal signature score in the epithelial cell sub-clusters. (iii) KDM5B expression in the epithelial cell sub-clusters. (iv, v) AUCell scores reflect the activity of KDM5B(+) and KDM5B(−) regulons in a given cell. d Volcano plots for differentially expressed genes from bulk RNA-Seq data for RT4 cells treated with the KDM5Bi C70 or an FGFRi. e Dot representation of GSEA AUCs for enriched vs. repressed Hallmark gene sets in RT4 cells treated with C70 and FGFRi See the legend of Fig. 1f, g. f Heatmaps of the ATAC-seq signal profiles in RT4 cells treated with the KDM5i C70 or with DMSO as a control, centered on transcriptional start sites. g ATAC-seq and RNA-Seq peak profiles at the interferon-inducible IFI27 and HLA-DQA1 gene loci in RT4 cells treated either with DMSO as a control or the KDM5 inhibitor C70. Pale blue rectangles highlight regions around transcriptional start sites.

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