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Updated: Jul 8, 2026
Intramucosal Inoculation of Squamous Cell Carcinoma Cells in Mice for Tumor Immune Profiling and Treatment Response Assessment
Published on: April 22, 2019
Reshaping the Immune Microenvironment by Targeting DKK1 to Enhance Combination Immunotherapy Efficacy in Head and
Fei Wang1, Minzhu Yan1, Xuelin Dong2
1Department of Otolaryngology, Head and Neck Surgery, Shanghai General Hospital of Nanjing Medical University, 200080 Shanghai, China.
Background:
Head and neck squamous cell carcinoma (HNSCC) is a common malignancy with high morbidity and mortality. Despite advances in immunotherapy, including the advent of immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1), only a subset of patients achieves significant benefit. This study aimed to evaluate the prognostic significance of Dickkopf-related protein 1 (DKK1), a potential modulator of the tumor immune microenvironment (TME), and to assess the therapeutic impact of combining DKK1 inhibition with ICIs.
Methods:
Data from The Cancer Genome Atlas (TCGA) and a clinical cohort of 62 patients with HNSCC from Shanghai General Hospital were used to analyze DKK1 expression and its association with prognosis and immune cell infiltration. Tumor immune organoids were constructed by co-culturing tumor and immune cells from patient samples to mimic the TME and evaluate the effects of anti-DKK1 therapy. A preclinical mouse model using the MOC2 (mouse oral carcinoma 2) cell line was also used to test the therapeutic efficacy of combined anti-DKK1 and anti-PD1 treatment. Immune cell composition was analyzed using immunohistochemistry, immunofluorescence, and flow cytometry.
Results:
High DKK1 expression was found to correlate with poor patient prognosis and an immunosuppressive TME, characterized by reduced CD8+ T cell infiltration and increased myeloid-derived suppressor cells (MDSCs). In tumor immune organoids, anti-DKK1 treatment reduced organoid growth. In vivo, combined anti-DKK1 and anti-PD1 treatment led to significantly greater tumor growth inhibition compared to monotherapies, increased CD8+ T cell activity, and decreased MDSC levels, thereby creating an immune-stimulatory environment.
Conclusions:
DKK1 drives immune suppression in HNSCC and represents a promising therapeutic target. Tumor immune organoids offer a robust platform for studying tumor-immune interactions and evaluating combination immunotherapies. Combining anti-DKK1 and anti-PD1 treatment approaches has the potential to enhance antitumor immunity and improve outcomes in patients with HNSCC.
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