Table 2 Studies related to the role of exhausted NK cells in AML

The increased expression of KIR activating receptors in ALL patients leads to the hyperactivation of these cells following the encounter with leukemic cells and further the exhaustion of NK cells and the progression of cancer

[64]

Some fungal infections, such as A. fumigatus, cause exhaustion in NK cells derived from AML patients and significantly inhibit their cytotoxic activity against leukemic cells

[65]

The frequency and absolute number of CD56⁺CD16⁺ NK cells in the peripheral blood of AML patients significantly decreased compared to normal subjects

NK cells expressing NKG2D, NKp46, and CD161 were significantly reduced in patients compared to normal subjects

[66]

NK cells in the peripheral blood of AML patients are in an exhaustion state

NK cells in the bone marrow mainly have a terminally differentiated phenotype, which correlates with low patient survival

[67]

Circulating NK cells in AML patients had many functional defects associated with excessive maturation and significant reduction of NKG2D and NKp30 expression

In patients who responded to chemotherapy, the functional responses of NK cells were restored

[68]

The expression of TIM-3 on NK cells and blasts in the bone marrow of AML patients can be used as a prognosis marker

[69]

Chronic activation of NK cells through the IL-15/mTOR pathway is one of the NK cell exhaustion mechanisms in AML models

A similar phenomenon was observed in NK cells derived from AML patients in vitro

[70]

Targeting the PVRIG/PVRL2 axis in AML patients is an efficient immunotherapeutic approach

[71]

NK cells in contact with leukemic cells in the C1498 murine AML model acquire the PD-1 molecule from leukemic cells through the Trogocytosis mechanism in a SLAM receptor-mediated manner

[72]

They showed that the success of leukemia treatment using the anti-PD-L1 antibody in PD-L1⁻ leukemia is due to the targeting of exhausted NK cells that express PD-L1

[73]

Blockade of PD-L1 in murine models of AML prevented the exhaustion of NK cells and increased their anti-leukemic activity

[74]

B7-H3-expressing NK cells increased in the peripheral blood of patients, which was associated with poor prognosis

Inhibition of B7-H3 enhanced the cytotoxic activity of NK cells, both in vitro and in vivo

[75]

Blockade of CD155/CD122 on leukemic cells by Flt3 inhibitors increased the cytotoxic activity of NK cells against these cells

[76]

TIGIT was upregulated on NK cells and bone marrow samples derived from AML patients after allogeneic transplantation. This was associated with the downregulation of NK cells in the bone marrow

[77]

TIGIT, CD39, and A2AR checkpoints are essential in inhibiting the activities of NK cells in both peripheral blood and bone marrow

Blockade of these checkpoints increased the cytotoxic activity of NK cells

[78]

The expression of TIM-3 in NK cells in newly diagnosed AML patients was associated with a poor prognosis and had prognostic significance

[79]

Newly diagnosed AML patients have a higher frequency of NK cells expressing TIGIT, PD-1, and TIM3 than normal subjects, which was associated with a poor prognosis

The expression of these checkpoints was associated with low cytotoxicity, and their inhibition increased the function of NK cells

[80]

TIM-3 expression in NK cells correlates with high functional capacity and better clinical outcomes in AML patients

TIGIT was intact, and PD-1 decreased in patients-derived NK cells compared to healthy donors

Blockade of TIM-3 (but not TIGIT and PD-1) inhibited the secretion of IFN-γ in NK cells following stimulation

[81]

The use of anti-NKG2A antibodies causes the activation of NK cells and tumor regression in a mouse model of AML

[82]

The interaction of the OX40 molecule on leukemic cells with the OX40L checkpoint causes the activation of NK cells and eliminates leukemic cells in AML patients

[83]

Transposon-engineered CAR-NK cells could efficiently target and destroy CLL-1-expressing AML cell lines, primary AML cells, and even leukemia stem cells

[84]