Epstein-Barr-virus-specific functional antibody signatures in the context of nasopharyngeal carcinoma development.

BACKGROUND: Nasopharyngeal carcinoma (NPC) in endemic areas is strongly linked to Epstein-Barr virus (EBV) infection. EBV-specific immunoglobulin (Ig)A and IgG titers have been used for diagnosis and prognosis, but their full potential for prediction and protection remains unclear. METHODS: We analyzed samples from 353 individuals, including patients with NPC at diagnosis or patients with NPC years prior to diagnosis, matched controls, and family members from NPC multiplex families from Taiwan, along with 50 patients with NPC from Singapore with survival data. We used systems serology, a comprehensive approach to assess antibody subclass, isotype, and fragment crystallizable gamma receptor (FcγR) binding, along with effector functions such as complement deposition, cellular phagocytosis, and natural killer (NK) cell activation. FINDINGS: Patients with NPC showed a broad expansion of antibody levels, FcγR binding, and Fc effector functions, especially neutrophil phagocytosis and complement deposition, compared to controls. Prior to NPC onset, individuals exhibited elevated EBV-specific IgM levels and higher FcγRIIA and FcγRIIIB binding, suggesting an early immune response to viral activity. IgMs appeared as potential correlative markers for NPC. In contrast, controls showed increased IgG2 levels and FcγRIIB binding, indicating lower inflammatory responses. On a per-antibody level, controls exhibited stronger Fc effector functions, suggesting a protective role in preventing NPC. Additionally, we identified a multivariate antibody signature associated with survival after treatment. CONCLUSIONS: This study provides valuable insights into EBV-specific antibodies as predictive biomarkers of NPC progression, offering opportunities for improved disease management. FUNDING: This work was supported by the Ragon Institute of Mass General, MIT, and Harvard with support from the National Cancer Institute (CA264646 to E.W.N.).