Cancer-Associated Fibroblast-Driven Progression of HPV+ Head and Neck Cancer with Organoid Models

Human papillomavirus-positive head and neck cancer (HPV+ HNC) is a distinct tumor entity that differs significantly from HPV-negative HNC (HPV- HNC) in clinical characteristics, genetic variations, and biological behavior. Focusing on the disease-specific features of HPV+ HNC is crucial for understanding its mechanisms of occurrence and progression as well as for advancing therapeutic strategies. Compared with HPV- cases, we found that HPV+ HNCs were enriched in cancer-associated fibroblasts (CAFs), and CAFs contribute significantly to the poor prognosis of HPV+ HNCs. To better explore the interaction between HPV+ HNCs and CAFs, we pioneered the development of 5 HPV+ HNC patient-derived organoid (PDO) models, which faithfully recapitulate the HPV infection status and the distinct drug responses of HPV+ HNCs. Using the generated HPV+ PDOs, we discovered that CAFs significantly enhanced HPV16 E7 expression in HPV+ cases while also promoting proliferation, stemness, and drug resistance. Moreover, our data showed that interleukin-6 (IL6), secreted by CAFs, regulates the activation of the hypoxia-inducible factor 1A (HIF1A) pathway in HPV+ cases. Drugs targeting HIF1A and the IL6 receptor significantly reduce HPV16 E7 expression and the proliferation of HPV+ HNC PDOs. These findings uncover unique cellular and molecular factors that drive the malignant progression of HPV+ HNC and hold promise for the development and application of novel therapeutic strategies for this disease.