A Humanized Mouse Model of Oral Squamous Cell Carcinoma for Investigating Resistance to Anti-PD1 Immunotherapy
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Updated: Sep 15, 2025
Intramucosal Inoculation of Squamous Cell Carcinoma Cells in Mice for Tumor Immune Profiling and Treatment Response Assessment
Published on: April 22, 2019
Abstract:
Immunotherapy has transformed cancer therapeutics; however, its impact on oral squamous cell carcinoma (OSCC) remains limited due to acquired resistance, including to Pembrolizumab. To better understand this challenge, we develop a humanized mouse model using immune-deficient NCG mice engrafted with human peripheral blood mononuclear cells (hPBMC), followed by orthotopic implantation of head and neck squamous cell carcinoma (HNSCC) stem cells. This model closely mimics the human tumor-immune microenvironment, showing aggressive tumor growth and metastasis. Pembrolizumab treatment significantly decreases CD8+ T cells, dendritic cells, and MHC-class-I expression at tumor sites, which are related to immunotherapy resistance. Further, pembrolizumab treatment confirms the elevated PD-L1 levels, immune evasion pathways and downregulation of MHC-class-I. qPCR further validates human-specific HLA expression. Our model offers a valuable tool for studying immunotherapy resistance and advancing treatment strategies in OSCC and could be useful for other cancers.
Insights
This study developed a humanized mouse model to investigate immunotherapy resistance in oral squamous cell carcinoma (OSCC). The model revealed how Pembrolizumab affects immune cells and highlights pathways contributing to treatment failure in OSCC.
Area of Science:
- Oncology
- Immunology
- Translational Medicine
Background:
- Immunotherapy has revolutionized cancer treatment but shows limited efficacy in oral squamous cell carcinoma (OSCC) due to acquired resistance.
- Pembrolizumab, a key immunotherapy drug, faces challenges in treating OSCC, necessitating a deeper understanding of resistance mechanisms.
Purpose of the Study:
- To develop a humanized mouse model that accurately replicates the human tumor-immune microenvironment in head and neck squamous cell carcinoma (HNSCC).
- To investigate the mechanisms of immunotherapy resistance, specifically to Pembrolizumab, in OSCC using the developed model.
Main Methods:
- Created a humanized mouse model by engrafting immune-deficient NCG mice with human peripheral blood mononuclear cells (hPBMC).
- Orthotopically implanted HNSCC stem cells into the humanized mice to establish tumors.
- Administered Pembrolizumab and analyzed changes in immune cell populations (CD8+ T cells, dendritic cells), MHC-class-I expression, PD-L1 levels, and immune evasion pathways via qPCR and other techniques.
Main Results:
- The humanized model demonstrated aggressive tumor growth and metastasis, closely mimicking human OSCC.
- Pembrolizumab treatment led to a significant decrease in CD8+ T cells, dendritic cells, and MHC-class-I expression at tumor sites.
- Elevated PD-L1 levels, activation of immune evasion pathways, and downregulation of MHC-class-I were observed following Pembrolizumab treatment, confirming resistance mechanisms.
Conclusions:
- The developed humanized mouse model is a valuable tool for studying immunotherapy resistance in OSCC.
- The findings provide insights into the molecular and cellular mechanisms underlying Pembrolizumab resistance in OSCC.
- This model holds potential for advancing treatment strategies for OSCC and other cancers exhibiting immunotherapy resistance.
