HPV6/11 Persistence and Treatment-Associated Immune Remodeling in Recurrent Respiratory Papillomatosis: A Cross-Cohort Transcriptomic Analysis

Recurrent respiratory papillomatosis (RRP), caused mainly by human papillomavirus types 6 and 11 (HPV6/11), can persist despite the absence of recognized systemic immunodeficiency. We reanalyzed three transcriptomic datasets using the same predefined immune-gene programs: paired papilloma and autologous laryngeal mucosa from 12 patients, single-cell RNA sequencing from papillomas of four RRP donors and pharyngopalatine mucosa from three controls, and paired papilloma samples from 17 patients before and after INO-3107, a DNA immunotherapy encoding HPV6/11 antigens and interleukin-12. In untreated tissue, cluster of differentiation 8 (CD8)- and natural killer (NK)-associated cytotoxic program scores were lower and the transforming growth factor beta (TGF-β) suppressive program score was higher, reproducing findings from the same cohort. The lower cytotoxic pattern was not reproduced within the recovered combined T-cell and NK-cell population, although no single-cell comparison remained significant after correction for multiple testing. After INO-3107, CD8- and NK-associated cytotoxic, T helper 1 (Th1)/interferon gamma (IFN-γ), and C-X-C motif chemokine receptor 3 (CXCR3)-associated trafficking program scores increased significantly, whereas TGF-β and M2-like suppressive programs showed no comparable statistically supported change. Together, these findings show that different components of the local immune response do not change in parallel and support a model of selective treatment-associated immune remodeling. This pattern may inform future biomarker and combination-treatment studies.