Abstract
ObjectiveThe 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.MethodsThe 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.ResultsDiverse 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.ConclusionDysregulation 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.
Highlights
Bladder cancer (BLCA) ranks as the 10th most common cancer with a high risk of recurrence [1]
The fractions of memory activated CD4+ T cells, activated NK cells and macrophages M0/M1/M2 were consistently higher in muscle-invasive bladder cancer (MIBC) than in non-muscle-invasive bladder cancer (NMIBC), whereas the fraction of resting memory CD4+ T cells was lower in MIBC (Figure 1B)
292 BLCA samples were selected for subsequent analysis (Supplementary Figure 1A)
Summary
Bladder cancer (BLCA) ranks as the 10th most common cancer with a high risk of recurrence [1]. The treatment and prognosis for NMIBC and MIBC are very different. If the resected tumor is high-grade T1 or carcinoma in situ, treatment entails intravesical therapy with Bacillus CalmetteGuérin (BCG). This disease is characterized by low rate of mortality but high rate of recurrence. MIBC patients are recommended to receive radical cystectomy with neoadjuvant chemotherapy, but the disease has a high rate of metastasis and mortality [3]. It is urgent to investigate the mechanistic determinants and molecular differences involved in malignant progression from NMIBC to MIBC, which may reveal effective biomarkers for early diagnosis, outcome prediction and target treatment
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