Pro-inflammatory cells sustain leukemic clonal expansion in T-cell large granular lymphocyte leukemia

Abstract

T-cell Large Granular Lymphocyte Leukemia (T-LGLL) is a chronic lymphoproliferative disorder characterized by the clonal expansion of T-LGL. Immunophenotypic and genotypic features contribute to discriminate symptomatic (CD8+ STAT3 mutated T-LGLL) from clinically indolent patients, this latter group including CD8+ wild type (wt), CD4+ STAT5B mutated and wt cases. T-LGL lymphoproliferation is sustained both by somatic gain-offunction mutations (i.e. STAT3 and STAT5B) and by pro-inflammatory cytokines, but little information is available on the activity of T-LGLL non leukemic cells. In this study, we characterized pro-inflammatory cells in peripheral blood of T-LGLL patients and analyzed their role in supporting the leukemic growth. In symptomatic patients we found that cell populations not belonging to the leukemic component showed a discrete pro-inflammatory pattern. In particular, CD8+ STAT3 mutated cases showed skewed Th17/Treg ratio and an abnormal monocyte populations’ distribution characterized by increased intermediate and non-classical monocytes. We also demonstrated that monocytes released high levels of IL-6 after CCL5 stimulation, a chemokine specifically expressed only by leukemic LGL. Conversely, in asymptomatic cases an altered distribution of monocytes populations was not detected. Moreover, T-LGLL patients’ monocytes showed abnormal activation of signaling pathways, further supporting the different pathogenetic role of monocytes in patients with discrete clinical settings. Altogether, our data contribute to deepen the knowledge on the different cell subtypes in TLGLL, particularly focusing on non-leukemic cell populations and thus offering the rationale for new therapeutic strategies.