Immune Deficiency/Dysregulation-Associated EBV-Positive Classic Hodgkin Lymphoma.

Area of Science:

• Hematology
• Immunology
• Oncology

Background:

• Immune deficiency/dysregulation presents a critical unmet need in classic Hodgkin lymphoma (cHL).
• Epstein-Barr virus (EBV) is a key driver in high-risk cHL, manipulating immune responses and tumor microenvironments.
• EBV-positive cHL in immunosuppressed populations has distinct molecular features compared to EBV-negative cHL.

Purpose of the Study:

• To review the etiological role of EBV in cHL pathogenesis within immune-dysregulated settings.
• To explore disparities in immune contexture and molecular hallmarks of EBV-associated cHL.
• To highlight the need for revised classification and therapeutic strategies targeting viral and immune complexities.

Main Methods:

• Literature review synthesizing current knowledge on EBV's role in cHL.
• Analysis of distinct molecular hallmarks and immune evasion mechanisms in EBV-positive cHL.
• Discussion of therapeutic challenges and future directions, including WHO classification implications.

Main Results:

• EBV oncoproteins exploit immune vulnerabilities, activate NF-κB, and promote immune suppression via PD-L1.
• EBV-positive cHL shows reduced somatic mutations and unique HLA associations.
• HIV co-infection exacerbates cHL pathogenesis, leading to M2 macrophage dominance and T-cell exhaustion.

Conclusions:

• EBV-associated cHL warrants reclassification as a distinct subset, integrating viral status and immune biomarkers.
• Current therapies are inadequate for addressing the viral and immune complexities in this high-risk group.
• Urgent priorities include epidemiological studies, development of virus-targeted therapies, and personalized treatment regimens.