A Humanized Mouse Model of Oral Squamous Cell Carcinoma for Investigating Resistance to Anti-PD1 Immunotherapy

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.