Peripheral blood immune profiling reveals key signatures in newly diagnosed NK/T cell lymphoma patients.

RATIONALE: Natural killer/T-cell lymphoma (NKTCL) is an aggressive Epstein-Barr virus (EBV)-associated non-Hodgkin lymphoma with a poor prognosis. Recent genomic and transcriptomic studies of tumor tissues have advanced our understanding of NKTCL pathogenesis, but the systemic immune profile at initial diagnosis remains incompletely elucidated.

METHODS

In this study, we characterized the immune landscape of peripheral blood mononuclear cells (PBMCs) from 20 newly diagnosed NKTCL patients and 12 healthy donors using single-cell RNA sequencing and confirmed our results through flow cytometry and PrimeFlow.

RESULTS

We identified a distinct proliferative-NK/T (Proli-NK/T) cell subset in NKTCL, characterized by high expression of cell cycle-related genes but lacking a malignant phenotype. Additionally, we observed a reduction in total and classical memory B cells, accompanied by enrichment of apoptosis and cell differentiation signatures. NK cells showed increased expression of HLA class II and activation markers, along with enhanced predicted interactions with CD4+ T cells. The decrease of naive CD4+ T cells might imply their skewed differentiation into Th1 and Th17 cells, while expansion of granzyme K (GZMK+)-expressing CD8+ central memory T cells was associated with interferon-γ-driven responses. Patients with a high intracellular EBV load exhibited accumulation of highly cytotoxic CD56dim _PTPRCAP NK cells and GZMK+ GZMB+ CD8+ effector memory T cells, along with a marked depletion of memory B cells. This implies a correlation between intracellular EBV burden and peripheral immune dysregulation in NKTCL.

CONCLUSIONS

We have uncovered the dynamic changes in PBMCs of newly diagnosed NK/T cell lymphoma patients and identified specific characteristics in patients with high intracellular EBV levels. Our findings provide new insights into the immunopathogenesis of NKTCL, offering valuable information for immune-based stratification and the development of therapeutic strategies.