Chemokine Ligand 13 Expression is Abundant in the Tumor Microenvironment and Indicates Poor Prognosis of Kidney Clear Cell Carcinoma

Abstract

The chemokine ligand 13-chemokine receptor 5 (<i>CXCL13-CXCR5</i>) axis has been characterized as a critical tumor-promoting signaling pathway in the tumor microenvironment (TME) in multiple types of solid tumors. In this study, we analyzed the expression profile of <i>CXCL13</i> in <i>kidney clear cell carcinoma</i> (KIRC) and its correlation with tumor-infiltrating immune cells (TIICs). A monoclonal antibody against CXCL13 with high affinity and purity was generated in our lab for western blot and immunohistochemistry (IHC). Bioinformatic analysis was performed based on bulk-seq data from the Cancer Genome Atlas (TCGA)-KIRC and single-cell RNA-seq data from scRNASeqDB and PanglaoDB. Results showed that high <i>CXCL13</i> expression in TME was associated with shorter progression-free survival (PFS), disease-specific survival (DSS), and overall survival (OS). KIRC cell lines, as well as several other cancer cell lines, had negative <i>CXCL13</i> expression. IHC staining from the Human Protein Atlas (HPA) and our tissue array indicated that CXCL13 might be mainly expressed by TIICs, but not KIRC tumor cells. <i>CXCL13</i> expression was strongly and positively correlated with γδ T cell abundance in TME. Besides, γδ T cell infiltration was associated with poor survival of KIRC. Methylation 450k array data showed that <i>CXCL13</i> promoter hypomethylation was common in TIICs. The methylation level of cg16361705 within the <i>CXCL13</i> promoter might play an important role in modulating <i>CXCL13</i> transcription. In conclusion, our study revealed that <i>CXCL13</i> expression and γδ T cell infiltration in TME is associated with unfavorable survival of KIRC. TIICs, most possibly γδ T cells, are the dominant source of CXCL13 in KIRC TME.