DKK1 Impairs the Tumor Response to αPD‐1 Immunotherapy by Inactivating CD8+ T Cells and Recruiting MDSC Cells in HNSC

Abstract

AbstractThe utilization of immune checkpoint inhibitors (ICIs) has received authorization for the treatment of head and neck squamous cell carcinoma (HNSC) and various other tumor types. However, a large proportion of HNSC patients exhibit unresponsiveness to ICIs. Dickkopf‐1, a secreted protein with pivotal functions in Wnt signaling pathways, is increasingly recognized for its role in modulating anti‐tumor immunity. In this study, the authors employed TCGA and GEO datasets to investigate the correlation between tumoral DKK1 expression and survival outcomes, as well as the suppressive nature of the tumor immunosuppressive microenvironment (TIME) in HNSC patients. The findings reveal a strong association between elevated DKK1 expression in HNSC tumors and poorer survival rates, along with an immunosuppressive TIME. In vivo studies utilizing subcutaneous tumor graft mouse models demonstrate that knockdown of DKK1 inhibit the growth of HNSC tumor cells in a CD8+ T cell‐dependent manner. Additionally, an inverse relationship between DKK1 expression and CD8+ T cell infiltration and activation is observed, while a positive correlation is observed with infiltration of myeloid‐derived suppressor cells (MDSCs) and CD8+ T cell exhaustion. Moreover, combining DKK1 knockdown with neutralizing antibodies against PD‐1 significantly suppress the growth of HNSC cells. Consequently, The study proposes DKK1 as a promising target for immunotherapy to enhance PD‐1 blockade therapy in HNSC. These findings show that DKK1 can thus be regarded as a potential target for immunotherapy and need further study.