Unraveling the prognostic significance and molecular characteristics of tumor-infiltrating B lymphocytes in clear cell renal cell carcinoma through a comprehensive bioinformatics analysis

Abstract

Introduction: Clear cell renal cell carcinoma (ccRCC) is a prevalent subtype of kidney cancer that exhibits a complex tumor microenvironment, which significantly influences tumor progression and immunotherapy response. In recent years, emerging evidence has underscored the involvement of tumor-infiltrating B lymphocytes (TIL-Bs), a crucial component of adaptive immunity, and their roles in ccRCC as compared to other tumors. Therefore, the present study endeavors to systematically explore the prognostic and molecular features of TIL-Bs in ccRCC.

Methods: Initially, xCell algorithm was used to predict TIL-Bs in TCGA-KIRC and other ccRCC transcriptomic datasets. The Log-Rank test and Cox regression were applied to explore the relationship of B-cells with ccRCC survival. Then, we used WGCNA method to identify important modules related to TIL-Bs combining Consensus subcluster and scRNA-seq data analysis. To narrow down the prospective biomarkers, a prognostic signature was proposed. Next, we explored the feature of the signature individual genes and the risk-score. Finally, the potential associations of signature with clinical phenotypes and drugs were investigated.

Results: Preliminary, we found ccRCC survival was negatively associated with TIL-Bs, which was confirmed by other datasets. Afterwards, ten co-expression modules were identified and a distinct ccRCC cluster was subsequently detected. Moreover, we assessed the transcriptomic alteration of B-cell in ccRCC and a relevant B-cell subtype was also pinpointed. Based on two core modules (brown, red), a 10-gene signature (TNFSF13B, SHARPIN, B3GAT3, IL2RG, TBC1D10C, STAC3, MICB, LAG3, SMIM29, CTLA4) was developed in train set and validated in test sets. These biomarkers were further investigated with regards to their differential expression and correlation with immune characteristics, along with risk-score related mutations and pathways. Lastly, we established a nomogram combined tumor grade and discovered underlying drugs according to their sensitivity response.

Discussion: In our research, we elucidated the remarkable association between ccRCC and B-cells. Then, we detected several key gene modules, together with close patient subcluster and B-cell subtype,which could be responsible for the TIL-Bs in ccRCC. Moreover, we proposed a 10-gene signature and investigated its molecular features from multiple perspectives. Overall, understanding the roles of TIL-Bs could aid in the immunotherapeutic approaches for ccRCC, which deserve further research to clarify the implications for patient prognosis and treatment.

Keywords: biomarker; clear cell renal cell carcinoma (ccRCC); gene signature; prognosis; tumor microenvironment; tumor-infiltrating B lymphocytes (TIL-Bs).