Characterizing tumor microenvironment heterogeneity in EBV⁺ nTNKL vs ENKTL using spatial transcriptomics and MIF

Area of Science:

• Hematology
• Oncology
• Immunology

Background:

• Epstein-Barr virus (EBV)-positive nodal T/NK-cell lymphoma (EBV+ nTNKL) is a rare entity distinct from Extranodal NK/T-cell lymphoma (ENKTL).
• The biology and clinical course of EBV+ nTNKL remain largely unknown compared to ENKTL.

Purpose of the Study:

• To investigate the molecular and immunological differences between EBV+ nTNKL and ENKTL.
• To characterize the clinical features and outcomes of EBV+ nTNKL patients.

Main Methods:

• Spatial transcriptomics and multiplex immunofluorescence were used to analyze ENKTL and EBV+ nTNKL specimens.
• A retrospective clinical cohort of 14 EBV+ nTNKL patients was analyzed.

Main Results:

• EBV+ nTNKL, of T-cell origin, exhibits reduced tumor burden, B-cell enrichment, and an immune-active microenvironment with cytotoxic T cells and PD-1/PD-L1 expression.
• ENKTL, of NK-cell origin, shows higher malignant cell density, neutrophil enrichment, and an immune-desert phenotype.
• Distinct intercellular communication pathways were identified: TGF-β/BMP in ENKTL and CXCL/CCL-GPCR in EBV+ nTNKL.
• EBV+ nTNKL patients frequently experienced hemophagocytic lymphohistiocytosis and had poorer survival, though some responded to immunotherapy.

Conclusions:

• This study elucidates the distinct immunologic and molecular landscapes of ENKTL and EBV+ nTNKL.
• Findings highlight the role of EBV latency and tissue context in shaping lymphoma ecology.
• Results suggest potential for subtype-tailored therapeutic strategies, including immune checkpoint inhibitors and CAR-T therapy.