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. 2022 Dec 1:21:74-85.
doi: 10.1016/j.csbj.2022.11.052. eCollection 2023.

Landscape of the intratumroal microenvironment in bladder cancer: Implications for prognosis and immunotherapy

Zichen Bian  1 , Jia Chen  1 , Chang Liu  1 , Qintao Ge  1 , Meng Zhang  1   2 , Jialin Meng  1 , Chaozhao Liang  1
Affiliations

Landscape of the intratumroal microenvironment in bladder cancer: Implications for prognosis and immunotherapy

Zichen Bian et al. Comput Struct Biotechnol J. .

Abstract

Introduction: This study aims to present the landscape of the intratumoral microenvironment and by which establish a classification system that can be used to predict the prognosis of bladder cancer patients and their response to anti-PD-L1 immunotherapy.

Methods: The expression profiles of 1554 bladder cancer cases were downloaded from seven public datasets. Single-sample gene set enrichment analysis (ssGSEA), univariate Cox regression analysis, and meta-analysis were employed to establish the bladder cancer immune prognostic index (BCIPI). Extensive analyses were executed to investigate the association between BCIPI and overall survival, tumor-infiltrated immunocytes, immunotherapeutic response, mutation load, etc.

Results: The results obtained from seven independent cohorts and meta-analyses suggested that the BCIPI is an effective classification system for estimating bladder cancer patients' overall survival. Patients in the BCIPI-High subgroup revealed different immunophenotypic outcomes from those in the BCIPI-Low subgroup regarding tumor-infiltrated immunocytes and mutated genes. Subsequent analysis suggested that patients in the BCIPI-High subgroup were more sensitive to anti-PD-L1 immunotherapy than those in the BCIPI-Low subgroup.

Conclusions: The newly established BCIPI is a valuable tool for predicting overall survival outcomes and immunotherapeutic responses in patients with bladder cancer.

Keywords: AJCC, American Joint Committee on Cancer; Anti-PD-L1, Antitumor response to atezolizumab; BCG, Bacillus Calmette-Guerin; BCIPI, Bladder cancer immune prognostic index; Bladder cancer; CNVs, Copy number variations; FDA, Food and Drug Administration; FPKM, Fragments per kilobase per million; Genomic; ICI, Immune checkpoint inhibitor; IHC, Immunohistochemistry; Immunotherapy; MES, Mesenchymal transition; NES, Normalized enrichment score; Overall survival; RMA, Robust multiarray average; RMS, Restricted mean survival; TPM, Transcripts per kilobase million; ssGSEA, Single-sample GSEA.

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Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

None
Graphical abstract
Fig. 1
Fig. 1
The 33 immune-associated signatures-based indexes predict the overall survival of bladder cancer patients. (A) The flow displays the overall design of the current study. (B) Heatmaps displaying the normalized enrichment score (NES) between bladder cancer immune prognostic index (BCIPI)-high and -low subgroups in the TCGA-BLCA and GSE32894 cohorts. (C–F) Kaplan–Meier plot showing distinct overall survival outcomes between the BCIPI-high and BCIPI-low subgroups in the TCGA-BLCA, GSE13507, GSE31684, and GSE32894 cohorts. (G) Meta-analysis displaying the overall prognostic value of the BCIPI by synthesizing the hazard ratio (HR) values from four bladder cancer cohorts.
Fig. 2
Fig. 2
Restricted mean survival (RMS) difference between the bladder cancer immune prognostic index (BCIPI) and the integrated signature in TCGA-BLCA, GSE13507, GSE31684, and GSE32894 cohorts. The integrated signature was generated by combining the BCIPI with clinicopathological features. The RMS curves are made up of a series of points representing the RMS time of matched BCIPI and integrated signature. The difference in terms of the C-index between the two signatures was determined by the t-test.
Fig. 3
Fig. 3
The bladder cancer immune prognostic index (BCIPI)-high subgroup showed higher infiltration of immunocytes than the BCIPI-low subgroup. (A) Pathway enrichment differences between the bladder cancer immune prognostic index (BCIPI)-high and BCIPI-low subgroups revealed by Gene Set Enrichment Analysis (GSEA). (B) The infiltration difference of the 28 immunocytes between the BCIPI-High and BCIPI-Low subgroups in the TCGA-BLCA, GSE13507, GSE31684, and GSE32894 cohorts. (C–D) Kaplan–Meier and log-rank analyses revealed that higher expression of CD163 was significantly correlated with unfavorable prognosis of bladder cancer with early-stage disease (AJCC Ois + I + II). (E–F) Kaplan–Meier and log-rank analyses revealed that a higher percentage of CD8+ positive cells was significantly correlated with a favorable prognosis for bladder cancer. (G) Kaplan–Meier and log-rank analyses revealed that a higher percentage of PD-L1-positive cells was seemingly associated with an unfavorable prognosis of bladder cancer. AJCC, American Joint Committee on Cancer.
Fig. 4
Fig. 4
The bladder cancer immune prognostic index (BCIPI) is associated with the response to anti-PD-L1 immunotherapy. CD274 (PD-L1) was more highly expressed in the BCIPI-High subgroup than in the BCIPI-Low subgroup in the TCGA-BLCA (A), GSE13507 (C), GSE31684 (E), and GSE32894 (G) cohorts. Patients in the BCIPI-High subgroup were predicted to have better anti-PD-L1 treatment effects in the TCGA-BLCA (B), GSE13507 (D), GSE31684 (F), and GSE32894 (H) cohorts.
Fig. 5
Fig. 5
Genetic differences between the bladder cancer immune prognostic index (BCIPI)-high and BCIPI-low subgroups. (A) Oncoprint plot displaying the significantly differentially mutated genes between BCIPI-High and BCIPI-Low subgroups. (B–C) The distribution difference in Arm- (B) and Focal-level (C) copy number variations (CNVs), including amplification (Amp) and deletion (Del). (D) Kaplan–Meier plot and log-rank analyses displaying the survival difference between gene-altered (patients with mutations of significantly differentially mutated genes) and unaltered (patients without mutations of significantly differentially mutated genes) subgroups in the TCGA-BLCA cohort. (E) FGFR expression was more highly expressed in gene-altered (patients with mutations of significantly differentially mutated genes) than unaltered (patients without mutations of significantly differentially mutated genes) subgroups in the TCGA-BLCA cohort. (F) The lollipop plot displays the major mutated sites of FGFR in the BCIPH-High (down) and BCIPI-Low (up) groups.
Fig. 6
Fig. 6
Validation of bladder cancer immune prognostic index (BCIPI) in external cohort and comparison with proposed molecular subtypes. (A) Kaplan–Meier plot showing the prognostic value of BCIPI for overall survival in GSE32584. (B) Kaplan–Meier plot showing the prognostic value of BCIPI to overall survival in GSE48075. (C) Kaplan–Meier plot showing the prognostic value of BCIPI for tumor progression in E-MTAB-4321. (D) Sankey plot displaying the correlation between BCIPI subgroups and TCGA-BLCA molecular subgroups; Kaplan–Meier plot showing the distinct survival outcome of basal squamous, luminal, luminal-infiltrated, luminal-papillary, and neuronal subtypes. (E) Sankey plot displaying the correlation between BCIPI subgroups and Kamoun et al.’s consensus subtype, Kaplan–Meier plot showing the distinct survival outcome of stroma-rich, NE-like, LumU, LumP, LumNS, and Ba/Bq subtypes. (F) Sankey plot displaying the correlation between BCIPI subgroups and Hedegaard et al.’s consensus subtype; Kaplan–Meier plot showing the distinct survival outcome of Luminal, CIS-like, and basal-like subtypes.
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