Acute Myeloid Leukaemia Induces Natural Killer Cell Exhaustion through Inhibition of the PI3K-AKT Pathway

Natural killer (NK) cell exhaustion is associated with a poor prognosis in persistent infection and cancer. Determination and understanding of the mechanism of NK cell exhaustion in acute myeloid leukaemia (AML) patients may provide underlying principles for enhancing AML therapy. We investigated NK cell exhaustion in relapsed AML patients post allogeneic haematopoietic stem cell transplantation (allo-HSCT) based on phenotypic, functional, and RNA-sequencing (RNA-seq) analyses. Compared with those from the complete remission control (N=30) and healthy control (N=12) groups, NK cells from the relapsed group (N=30) were less mature, with a large CD56bright subset, high NKG2A expression, poor cytotoxicity, downregulation of the transcription factors Eomesodermin (EOMES) and T-bet, and cell cycle arrest in the G1 stage. NK cell exhaustion could be reversed once relapsed patients achieved remission. Furthermore, NK cells showed high NKG2A expression but normal cytotoxicity in minimal residual disease (MRD)-positive patients post allo-HSCT. Combined with in vitro and mouse model results, the data suggested that NK cell exhaustion was induced by persistent AML stimulation. Moreover, RNA-seq and western blot analyses showed that the phosphatidylinositol-3-kinase (PI3K)-AKT inhibition in exhausted NK cells was induced by AML and that PI3K-AKT activators could reverse NK cell exhaustion in vitro. Consequently, our studies highlight that AML induces NK cell exhaustion through the PI3K-AKT pathway.