Classic Hodgkin Lymphoma Beyond the Lymph Node: A Systemic Immunobiological Paradigm

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Classic Hodgkin lymphoma (cHL) traditionally viewed as nodal, but this overlooks its biological complexity.
• Malignant Hodgkin and Reed-Sternberg (HRS) cells orchestrate a complex tumor microenvironment.
• HRS cells secrete systemic factors influencing immune responses beyond lymph nodes.

Purpose of the Study:

• Reinterpret cHL as a systemic immunobiological disease.
• Explore molecular and immunological drivers of cHL.
• Develop advanced monitoring and treatment strategies.

Main Methods:

• Analysis of molecular signaling pathways (NF-κB, JAK/STAT).
• Assessment of immune checkpoint ligand expression.
• Measurement of circulating tumor DNA (ctDNA) and soluble mediators (TARC/CCL17).
• Peripheral immune profiling and functional imaging.

Main Results:

• HRS cells drive systemic immune reprogramming, including T-cell exhaustion and immunosuppressive myeloid cell expansion.
• ctDNA and TARC/CCL17 levels reflect systemic disease activity and tumor burden.
• Biological insights explain clinical features like B symptoms and treatment resistance.
• Multidimensional assessment integrating ctDNA, immune profiling, and imaging overcomes conventional staging limitations.

Conclusions:

• cHL should be viewed as a systemic immunobiological disease.
• Immune checkpoint inhibitors highlight the role of systemic immune dysregulation.
• Biomarker-driven strategies enable personalized medicine for cHL.
• A paradigm shift towards biology-driven precision medicine is crucial for cHL management.