Perturbed function of natural killer cells by inflammatory cytokines in acute (AML) and chronic (CML) myeloid Leukemias

Abstract Natural killer (NK) cells have the capacity to eliminate malignant cells by releasing cytotoxic granules. Indeed, mature NK cell counts are associated with favorable prognosis in AML and prolonged TKI-free remission in CML. However, NK cell maturation and anti-leukemic activity are suppressed during the disease, and the environmental drivers of this impairment remain unclear. Given an established role of inflammatory cytokines (particularly IL-1β, IL-6, and TNFα) in the progression of myeloid malignancies, we define their impact on NK cell function in chimeric mouse models of leukemia – Flt3-ITD/TET2, AML/ETO9a, Meis/Hox (AML), and BCR-ABL1 (CML), where NK cells do not carry the oncogene. Reflecting clinical observations, NK cell frequencies and numbers are reduced, implying oncogene-independent mechanisms of NK dysfunction in different leukemic subtypes. Moreover, both AML- and CML-exposed NK cells display immature phenotypes, diminished expression of activating receptors, and impaired ex vivo target-specific degranulation. The single cell RNA-seq analysis of CML-exposed NK cells confirmed decreased expression of NK maturation and cytotoxicity markers and upregulation of inhibitory receptors and genes associated with inflammatory cytokine response. Furthermore, IL-6-STAT3 and IL-1β/TNFα transcriptional signatures are enriched during the disease, which is likely to be triggered by leukemic cytokines. Thus, we next found that leukemic serum dampens NK cell degranulation ex vivo, compared to serum from control mice. These data suggest that soluble leukemic factors contribute to NK cell dysfunction and represent an optimal target for NK-boosting immunotherapies across different types of myeloid malignancies.