Uncovering the Functional Antibody Landscape in HPV-Associated Oropharyngeal Squamous Cell Carcinoma

Human papillomavirus (HPV) accounts for approximately 25–30% of head and neck squamous cell carcinomas (HNSCC), including 60–70% of oropharyngeal squamous cell carcinomas (OPSCC), a disease with rapidly increasing incidence. While antibodies to HPV antigens are proposed biomarkers, their functional relevance remains undefined. We applied systems serology to 182 individuals—including HPV⁺ OPSCC patients at diagnosis, post-treatment, and recurrence—to comprehensively profile antibody isotypes, Fc receptor (FcR) binding, and Fc mediated effector functions against HPV16 E2 and E7—all integrated with machine learning for feature selection. At diagnosis, HPV⁺ OPSCC patients exhibited robust IgG1-dominated responses with enhanced FcR binding and effector activity compared with controls. Antibody levels declined slowly after treatment but remained detectable for >700 days across modalities. Importantly, patients without recurrence demonstrated enriched E2-specific functional responses, particularly complement-fixing antibodies, broader cross-genotype reactivity, and more coordinated immune profiles, whereas recurrent cases showed diminished Fc-effector activity. These findings suggest that antibody quality and breadth, rather than magnitude alone, may contribute to durable remission. Our data identify E2-specific Fc-functional signatures as candidate biomarkers for recurrence risk and highlight humoral immunity as a potential axis for therapeutic development in HPV-driven malignancies.