B7x mediates resistance to immune checkpoint blockade, while combination therapy with B7x blockade overcomes resistance (IMAGE)
Caption
Analysis of complete responders and progressive disease patients with advanced or metastatic muscle-invasive bladder cancer (MIBC) treated with anti-PD-L1 blockade immunotherapy, stratified by B7x mRNA expression using a median cutoff (n = 96 patients per group). (A) The Kaplan–Meier survival curve comparing the overall survival of patients with high versus low B7x expression. Log-rank test was used. (B) The heatmap of clinical characteristics and bulk RNA-sequencing pathways of IMvigor210 patients stratified by B7x expression. Chi-squared or Fisher’s exact tests were applied. A, FGFR3 signaling; B, CD8 T effector cell; C, antigen presentation machinery; D, immune checkpoints; E, cell cycle; F, histones; G, DNA-damage repair; H, TGF-β signaling; I, fibroblast TGF-β response signature; J, epithelial–mesenchymal transition; K, angiogenesis. (C) The stacked bar graph depicting PD-L1 expression in immune cells (left) and tumor cells (right) in B7xhigh and B7xlow bladder cancer samples. Chi-squared tests were applied; ∗P < 0.02. (D) The violin plot showing neoantigen burden per megabase in B7xhigh and B7xlow tumors, with individual patients represented by dots. The Mann–Whitney U test was used. (E) Single-sample gene set enrichment analysis (ssGSEA) pathway enrichment scores for patients identified in panel A, displayed as a volcano plot with mean rank fold-change versus P value. Multiple Mann–Whitney U test was used (FDR q-value = 5%). (F) Experimental design schematic of B7x+ BBN963 tumor engraftment and treatment with B7x, PD-1, PD-L1, or CTLA-4 blockade monotherapy or combination therapies. (G) Mean (left) and individual (right) tumor volume tracing of B7x+ BBN963 tumors in immune-competent mice treated with ICB monotherapies or combination therapies. The Kruskal–Wallis test was used. Error bars represent the standard error of the mean. The data represent mean ± standard error of the mean. Corresponding P values are indicated throughout.
Credit
Marc C. Pulanco, Xiang Yu Zheng, Alexander Sankin, Deyou Zheng, Xingxing Zang
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