Acute Myeloid Leukemia Induces Natural Killer Cell Exhaustion via Inhibition of the PI3K-AKT Pathway

Acute myeloid leukemia (AML) relapse is associated with a poor prognosis. Natural killer (NK) cells therapy induce leukemia remission; however, NK cells were susceptible to be exhausted post infusion. Determination of the mechanism of NK cell exhaustion in AML patients may provide insights for enhancing AML therapy. Here, we investigated NK cell exhaustion in relapsed AML patients post allo-HSCT based on phenotypic, functional, and RNA sequencing analyses. Compared with those from the complete remission and healthy control groups, NK cells from the relapsed group exhibited less maturity, higher inhibitory receptor expression and poorer cytotoxicity. AML cells could induce NK cell exhaustion through inhibition of PI3K-AKT pathway. Activation of PI3K-AKT was effective to increase NK cell cytotoxicity in exhausted NK cells. Excessive activation of the NKG2A/HLA-E axis is responsible for the inhibition of the PI3K-AKT pathway. Anti-HLA-E restored NK cell cytotoxicity against AML by increasing the phosphorylation of AKT in exhausted NK cells and knockout of the klrc1 in NK92 cells increased the phosphorylation of AKT and cytotoxicity against THP-1 cells. Moreover, blocking NKG2A was effective in controlling NK cell exhaustion and promoting cytotoxicity in AML mice. In summary, AML cells induced NK cell exhaustion via excessive activation of NKG2A/HLA-E axis and inhibition on PI3K-AKT pathway. Blocking the NKG2A axis is an effective way to reverse the inhibition of PI3K-AKT signaling on exhausted NK cells.