Tumor Microenvironment (TME) Predicts Response to Immunotherapy in Muscle-Invasive Bladder Cancer (MIBC) Tumors - Expert Commentary

Gene expression profiling has successfully classified muscle-invasive bladder cancer (MIBC) tumors into distinct categories that differ in their genetic characteristics and tumor mutation burden (TMB). In addition to cancer-cell autonomous factors, the tumor microenvironment (TME) is a known key player in therapy response. The relationship between TME and different MIBC molecular subtypes is understudied.

A recent study by Cao et al. used publicly available MIBC molecular and clinical data to develop a TME-related signature (TMERS) and define its prognostic and predictive value. A TMRES score was derived from the expression of TME-related genes and differentially expressed between the immune and stromal-enriched patients. A nomogram was constructed to identify the independent predictive value of TMB and TMERS with other clinical factors on the prognosis of MIBC patients treated with immunotherapy. TMERS was dichotomized into high vs. low for downstream analyses.

The study has found that TCGA-BLCA patients with high TEMRS scores had significantly shorter overall survival. This was confirmed in other validation datasets. High TMERS was associated with high-risk molecular subtypes across different classifiers, e.g., basal squamous and neuronal subtypes in the TCGA classifier and basal/SCC-like subtype in the Lund classifier. High TEMRS also showed a significant negative correlation with TMB. Furthermore, TMERS remained an independent prognostic factor when combined with other clinicopathological characteristics and TMB. A nomogram including clinicopathological factors found that TMERS, TMB, pathological N stage, and age were the only four independent prognostic factors in MIBC patients.

Immunotherapy response rates were significantly higher among low TMERS patients than those with high TMERS patients across four independent transcriptomic cohorts with immunotherapy data (p-value < 0.00001). Of particular interest, the authors showed that low TMERS patients had significantly longer progression-free survival than high TMERS patients in the IMvigor210 cohort (log-rank test, p-value = 0.0441). 

This retrospective analysis identified a comprehensive tool appreciating the diversity of clinical, molecular, and immune features observed within MIBC tumors. These observations are particularly relevant for patients treated with immunotherapy. Prospective validation of different molecular subtypes as predictors of response to therapy is needed and should be incorporated into clinical trials.

Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine, New York City, New York


  1. Cao R, Yuan L, Ma B, Wang G, Tian Y. Tumour microenvironment (TME) characterization identified prognosis and immunotherapy response in muscle-invasive bladder cancer (MIBC). Cancer Immunol Immunother. 2021;70(1):1-18. PMID: 32617668

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