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

Qiwen Pan; Ruiqi Liu; Xinyue Zhang; Lingling Cai; Yilin Li; Pei Dong; Jianming Gao; Yang Liu; Liru He

doi:10.1177/17588359231217966

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

Ther Adv Med Oncol. 2023 Dec 25:15:17588359231217966. doi: 10.1177/17588359231217966. eCollection 2023.

Authors

Qiwen Pan¹, Ruiqi Liu¹, Xinyue Zhang¹, Lingling Cai¹, Yilin Li¹, Pei Dong², Jianming Gao¹, Yang Liu³, Liru He³

Affiliations

¹ Department of Radiation Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China.
² Department of Urology Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China.
³ Department of Radiation Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, No. 651, Dongfeng Road East, Guangzhou 510060, P. R. China.

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.

Keywords: antigen presentation; epigenetic modulators; immunotherapy; predictive biomarker; renal cell carcinoma; single-cell RNA-sequencing; tumor immune microenvironment.

Plain language summary

CXCL14 as potential predictor for immunotherapy response in kidney cancer Kidney-expressed chemokine (CXCL14) regulates immune cells. We studied how it affects the body’s immune response to kidney cancer based on public and private database and staining. We found that higher levels of CXCL14 in kidney cancer were linked to better patient survival. CXCL14 seems to help activate the immune system. When patients with high CXCL14 levels received immunotherapy, they tended to survive longer than those with low levels. Fibroblasts with CXCL14 were present in patients responding to immunotherapy. Further tests confirmed that high CXCL14 levels were related to more immune cells. CXCR4 may be its receptor in kidney cancer. This suggests that measuring CXCL14 levels could help predict how well a patient might respond to immunotherapy for kidney cancer.