Immunological dynamics in orthotopic versus 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. 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. In contrast, orthotopic (base of tongue, BOT) tumors exhibited a progressive decline in cytotoxic T cells and an accumulation of myeloid-derived suppressive cells, paralleling the immune desertification observed in advanced, immune-excluded human tumors. Additionally, our drug responsiveness analysis inferred that early-stage BOT models could more accurately replicate the response to PD1 blockade, whereas late-stage SC models could 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.