DKK1 affects survival of patients with head and neck squamous cell carcinoma by inducing resistance to radiotherapy and immunotherapy.

Abstract

Immune checkpoint inhibitors (ICIs) have been approved to treat various types of tumors, including head and neck squamous cell carcinoma (HNSC). However, most HNSC patients do not respond to ICIs. Radioimmunotherapy has been proposed to enhance the immune response rate in HNSC. Dickkopf-1 (DKK1), a secreted protein, plays important roles in the Wnt signaling pathways. Herein, we aimed to explore the effect of DKK1 on radioimmunotherapy in HNSC. We collected the gene expression profile and clinical information of HNSC patients from TCGA and GEO databases. The immune cell infiltration and immune score were assessed using R package CIBERSORT and ESTIMATE. The level of related pathways and biological processes were analyzed by GSEA. The signature scores of gene sets of interest were calculated by GSVA. We also performed cell viability and apoptosis assay, and clonogenic assay to investigate the radiation sensitivity of HSC-3 cells and CNE-2 cells after silencing DKK1 by siRNA. We found DKK1 was significantly higher expressed in HNSC, and closely correlated with patients' survival time, especially the patients who received radiotherapy. DKK1-knockdown HSC-3 cells or CNE-2 cells showed a decrease in cell viability and colony formation, and an increase in apoptotic rate after radiation. DKK1^high tumors showed a more immunosuppressive microenvironment with lower infiltration of T cells and higher infiltration of marrow-derived suppressor cells (MDSCs). Our data show that DKK1 can affect both radiotherapy and immunotherapy in HNSC, suggesting that DKK1 can be a potential target for radioimmunology in HNSC.