CXCL14 as a potential marker for immunotherapy response prediction in renal cell carcinoma

Abstract

Background: Epigenetic mechanisms play vital roles in the activation, differentiation, and effector function of immune cells. The breast and kidney-expressed chemokine (CXCL14) mainly contributes to the regulation of immune cells. However, its role in shaping the tumor immune microenvironment (TIME) is yet to be elucidated in renal cell carcinoma (RCC). Objectives: This study aimed to elucidate the role of CXCL14 in predicting the efficacy of immunotherapy in patients with RCC. Methods: CXCL14 expression and RNA-sequencing, single-cell RNA-sequencing (scRNA-seq), and survival datasets of RCC from public databases were analyzed, and survival was compared between different CXCL14 levels. The correlation between CXCL14 and immune infiltration and human leukocyte antigen (HLA) gene expression was analyzed with TIMER2.0 and gene expression profiling interactive analysis. Institutional scRNA-seq and immunohistochemical staining analyses were used to verify the relationship between CXCL14 expression level and the efficacy of immunotherapy. Results: CXCL14 was expressed in fibroblast and malignant cells in RCC, and higher expression was associated with better survival. Enrichment analysis revealed that CXCL14 is involved in immune activation, primarily in antigen procession, antigen presentation, and major histocompatibility complex assemble. CXCL14 expression was positively correlated with T-cell infiltration as well as HLA-related gene expression. Among the RCC cohort receiving nivolumab in Checkmate 025, the patients with CXCL14 high expression had better overall survival than those with CXCL14 low expression after immunotherapy. scRNA-seq revealed a cluster of CXCL14+ fibroblast in immunotherapy responders. Immunohistochemistry analysis verified that the patients with high CXCL14 expression had an increased proportion of high CD8 expression simultaneously. The expression level of CXCL14 was associated with CXCR4 expression in RCC. Conclusion: CXCL14 expression is associated with immunotherapy response in RCC. It is a promising biomarker for immunotherapy response prediction and may be an effective epigenetic modulator in combination with immunotherapy approaches.

The Chemokine CXCL14 as a Potential Immunotherapeutic Agent for Cancer Therapy

“…This possibility is further supported by the association of high CXCL14 expression with better patient survival in multiple cancers, including HNSCC and CxCa [ 41 ]. Furthermore, new evidence from Pan et al has shown that CXCL14 expression is associated with an enhanced response to immunotherapy in renal cell carcinoma [ 67 ]. Additionally, CXCL14 has several beneficial features as a therapeutic agent.…”

“…This could be a key advantage of using CXCL14 compared to other cytokines (e.g., IL-2), many of which have been shown to cause high toxicity or trigger immune suppression via regulatory T cells [ 69 ]. Lastly, CXCL14 has dual functions in enhancing antitumor responses by recruiting natural killer (NK) and T cells into the TME and upregulating MHC-I expression on tumor cells to enhance antigen presentation [ 40 , 42 , 67 ]. Thus, CXCL14 has great potential as an immunotherapeutic agent in novel combination immunotherapy with an ICI, particularly for ICI nonresponders.…”