Persistent infection with HPV causes nearly 5% of all cancers worldwide, including cervical and oropharyngeal cancers. Compared to HPV-negative (HPV−) head and neck squamous cell carcinomas (HNSCCs), HPV-positive (HPV+) HNSCCs exhibit a significantly improved treatment response; however, established treatment regimens were largely developed for HPV− disease. Effectively de-escalating therapy and optimizing treatment protocols to minimize toxicity for both HPV+ and HPV− tumors has been variably successful, in part due to the heterogeneity of cellular subpopulations. Single-cell RNA sequencing (scRNAseq) has primarily been used to define immune cell populations rather than the cell type of origin, epithelial cells. To address this, we analyzed published scRNAseq data of HPV+ and HPV− HNSCCs to distinguish epithelial tumor cell populations as a function of HPV status. We identified the transcriptome signatures, ontologies, and candidate biomarkers of newly identified epithelial subpopulations with attention to those that are shared or enriched in HPV+ or HPV− HNSCCs. We hypothesize that distinct epithelial cell populations and reprogramming in HPV− versus HPV+ HNSCC represent important components of the pro-tumor environment. These are described here as a foundation for the identification of new epithelial-cell-specific biomarkers, effectors, and candidate targets for optimizing the treatment of HNSCC.
