The investigators initially assembled a set of 32 genes associated with B cell exhaustion from published studies. These genes were used to categorize 399 patients with BC from The Cancer Genome Atlas (TCGA) cohort into two clusters (C1 and C2). Clustering was an independent predictor of prognosis (p < 0.05). Patients in C2 exhibited poorer prognosis and lower levels of tumor immune responses (p < 0.001). Zhou et al. subsequently analyzed available bulk and single-cell transcriptomic data from BC patients, resulting in an overlap of 39 genes that were consistently linked to B cell exhaustion. After constructing a list of gene pairs, twenty gene pairs were found to be significant predictors of prognosis. These data points were used to establish the B cell exhaustion-related score (BEXRS), which exhibited high predictive ability across different publicly available cohorts. The investigators also validated these findings experimentally using immunohistochemical staining and flow cytometry on BC tissues.
The investigators subsequently examined genomic data from the TCGA BC cohort and found that there was a negative correlation between BEXRS and total number of single nucleotide variants (p < 0.05), tumor purity (p < 0.01), cancer DNA fraction (p < 0.01), neoantigen load (p < 0.05), and tumor mutation burden (p < 0.05). Patients with low BEXRS also had a higher mutational frequency in FGFR3 and PIK3CA (p < 0.05). Using two computational algorithms (TIMER and XCELL), the investigators also found that BEXRS had a negative association with B cell infiltration levels in the tumor microenvironment (p < 0.001 for TIMER; p < 0.01 for XCELL). In two patient cohorts, patients with high BEXRS were less likely to benefit from ICI treatment (p < 0.001). However, there were no significant differences in the third cohort (p > 0.05).
These findings also provide new insights into the immune mechanisms linked to disease progression and outcomes. This B cell exhaustion gene signature is a potential prognostic biomarker in patients with BC.
Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine
References:
- Zhou R, Zhou J, Deng S, et al. Developing and experimental validating a B cell exhaustion-related gene signature to assess prognosis and immunotherapeutic response in bladder cancer. Gene. 2024;927:148634. doi:10.1016/j.gene.2024.148634
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