Overexpressing natural killer group 2 member A drives natural killer cell exhaustion in relapsed acute myeloid leukemia

Abstract Acute myeloid leukemia (AML) relapse is associated with poor prognosis. While natural killer (NK) cell therapy can induce leukemia remission, infused NK cells are prone to exhaustion. Elucidating the molecular mechanisms driving NK cell exhaustion in AML patients could provide critical insights for developing novel strategies to optimize NK cell-based immunotherapies. In this study, we systematically investigated NK cell exhaustion in relapsed AML patients following allogeneic hematopoietic stem cell transplantation (allo-HSCT) through phenotypic assessments, functional assays, and RNA sequencing analyses. Compared to NK cells from complete remission patients and healthy controls, NK cells from relapsed AML patients exhibited an exhausted phenotype, marked by reduced maturity, elevated expression of the inhibitory receptor NKG2A, impaired cytotoxicity, and suppression of the PI3K-AKT pathway. Notably, NKG2A expression levels on NK cells correlated with disease progression. Blockade or genetic knockout of NKG2A effectively reversed NK cell exhaustion both in vitro and in an AML mouse model. Furthermore, activation of the PI3K-AKT pathway significantly enhanced cytotoxicity in exhausted NK cells. We found that excessive activation of the NKG2A/HLA-E axis was associated with PI3K-AKT pathway inhibition, and blocking the NKG2A/HLA-E interaction or knocking out NKG2A restored AKT phosphorylation in exhausted NK cells. In summary, AML cells drive NK cell exhaustion through overactivation of the NKG2A/HLA-E axis and suppression of the PI3K-AKT pathway. Targeting the NKG2A/HLA-E axis represents a promising therapeutic approach to restore PI3K-AKT signaling and reverse NK cell exhaustion.