Immunological dynamics in orthotopic compared with subcutaneous murine models of HPV-positive oropharyngeal cancer

The necessity of reliable preclinical models for evaluating the efficacy of novel therapeutic strategies is imperative. Nevertheless, the degree to which tumor-bearing murine models represent the immunological characteristics of human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) has largely been unexplored. By utilizing single-cell RNA sequencing technology, our research elucidated that subcutaneous (SC) murine models more accurately reflect the early immunogenic phase of human HPV-positive OPSCC, marked by a stage-dependent increase in effector T-cell infiltration. By contrast, orthotopic (base of tongue, BOT) tumors exhibited a progressive decline of cytotoxic T cells and accumulation of myeloid-derived suppressive cells, paralleling the immune decrease observed in advanced, immune-excluded human tumors. Additionally, our drug responsiveness analysis indicated that early-stage BOT models more accurately replicate the response to PDCD1 blockade, whereas late-stage SC models more accurately mirror the response to CTLA4 blockade akin to human samples. Our findings provide pivotal insights into the suitability of murine models for the preclinical assessment of immunotherapies in HPV-positive OPSCC.