Dickkopf-1 is a Prognostic Biomarker of Head and Neck Squamous Cell Carcinoma that Correlates with Immune Infiltrates

Abstract

<h3>Purpose/Objective(s)</h3> Head and neck squamous cell carcinoma (HNSCC) is associated with high immune cell infiltration, and immunotherapy is currently one of the most promising treatments for HNSCC. Dickkopf-1 (DKK1), a Wnt-signaling inhibitor and mediator of immune activation, is highly associated with tumor progression and the tumor microenvironment and, thus, disease prognosis. However, the associations between DKK1 expression, HNSCC prognosis, and tumor-infiltrating lymphocytes remain unknown. <h3>Materials/Methods</h3> We investigated these relationships in this study by exploring DKK1-expression differences in multiple tumor tissues and normal tissues, using the TIMER, Oncomine, and UALCAN databases. We searched the Kaplan–Meier database to assess correlations between DKK1 mRNA-expression levels and clinical outcomes. Subsequently, we evaluate the correlation between DKK1 expression and tumor immune-cell infiltration using the TIMER platform and TISIDB website. In addition, we assessed DKK1, CD3, and CD4 expression in 27 head and neck tumor samples and DKK1 expression in 15 normal head and neck tissue samples by immunohistochemistry. Moreover, we used the cBioPortal and UCSC Xena databases to explore aberrant DKK1 expression during tumorigenesis. <h3>Results</h3> DKK1 significantly upregulated in HNSCC tissues versus normal tissues. DKK1 expression was related to the HNSCC tumor stage, tumor grade, histology, lymph node metastasis, and a poor clinical prognosis. DKK1 expression correlated negatively with CD3+ (P < 0.0001) and CD4+ (P < 0.0001) immune cell infiltration in HNSCC tumor tissues. Moreover, DKK1 closely correlated with genetic markers of various immune cells. The prognosis of HNSCC correlated negatively with DKK1 expression in immune cells. Copy-number variation and DNA methylation may promote abnormal DKK1 upregulation in HNSCC. These results help understand the role of DKK1 in HNSCC immunotherapy and provide a rationale for clinical research on treating HNSCC by targeting DKK1. <h3>Conclusion</h3> DKK1 may therefore serve as a prognostic indicator and a biomarker for immune infiltration in HNSCC, and potentially as a central target for improving the diagnosis and immunotherapy efficacy of HNSCC.