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Induction of Invasive Transitional Cell Bladder Carcinoma in Immune Intact Human MUC1 Transgenic Mice: A Model for Immunotherapy Development
Published on: October 30, 2013
Dysregulation of the Immune Microenvironment Contributes to Malignant Progression and Has Prognostic Value in Bladder
Zongtai Zheng1, Shiyu Mao1, Wentao Zhang1
1Department of Urology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
Objective:
The malignant progression from non-muscle-invasive bladder cancer (NMIBC) to muscle-invasive bladder cancer (MIBC) is common and has detrimental effect on patients. We aimed to elucidate the underlying mechanisms of the malignant progression from an immunological perspective and establish a reliable signature for prognostic prediction and immunotherapeutic strategies.
Methods:
The Cell Type Identification by Estimating Relative Subsets of RNA Transcripts algorithm was applied to the GSE32894 data set to identify the different tumor-infiltrating immune cells involved in NMIBC and MIBC. Using weighted gene correlation network analysis, survival analysis and least absolute shrinkage and selection operator Cox analysis, we established an immune prognostic signature (IPS) based on 14 overall survival-associated immune genes in The Cancer Genome Atlas (TCGA). Functional enrichment analyses and nomogram were performed to explore the potential effects and prognostic performance of the IPS. Furthermore, the RNA-sequence data from our center were used to validate the expression levels of the selected immune genes in BLCA samples.
Results:
Diverse proportions of macrophage subtypes were observed between NMIBC and MIBC. Patients with high risk scores had a worse prognosis than patients with low risk scores in training (TCGA) and validation data sets (GSE32894, GSE13507, and GSE48277). The IPS was a useful prognostic factor for patients treated with immunotherapy in the IMvigor210 trial. Hallmarks of multiple oncogenic pathways were significantly enriched in the high risk group. A novel nomogram model was established for prognostic predictions. The dysregulated expression of the selected immune genes between NMIBC and MIBC was also validated in BLCA samples.
Conclusion:
Dysregulation of the immune microenvironment promoted the malignant progression from NMIBC to MIBC. The IPS can stratify patients into different risk groups with distinct prognoses and immunotherapeutic susceptibility, thus facilitating personalized immunotherapy.
