Table 1 Studies related to the role of exhausted NK cells in CLL

Ammonium chloride can inhibit the cytotoxic activity of NK cells in vitro

[53]

The upregulation of circulating CD56⁺CD3⁻Tim-3⁺ exhausted NK cells in CLL patients was associated with the upregulation of CD56⁺CD3⁻Tim-3⁺ NK cells associated with disease progression

[54]

Anti-CD20 monoclonal antibodies ofatumumab or rituximab) can cause the exhaustion of NK cells in CLL patients through binding to CD16 on NK cells

[52]

Treatment of 55 relapsed/refractory and 50 untreated CLL patients with Ibrutinib was associated with increased effective NK cells compared to 20 normal subjects

[57]

The long-term treatment of CLL patients with Ibrutinib increased NK cells in peripheral blood, which was associated with a good prognosis

[58]

Leukemic B cells of CLL patients express significantly higher levels of Siglec-7 ligands than normal individuals, which was associated with poor disease prognosis

[59]

The expression of LAG3 was significantly increased in leukemic cells and NK cells and was associated with a poor prognosis

Inhibiting this checkpoint increased the cytotoxic activity of NK cells against leukemic cells

[60]

The upregulation of BTLA is detected in both leukemic cells and NK cells in untreated CLL patients, which was associated with a poor prognosis

Ex vivo blockade of BTLA led to the depletion of leukemic cells and enhanced cytotoxic function and cytokine secretion by NK cells

[61]

The expression of ILT2 was increased in the NK cells of CLL patients (n = 60), which was associated with a poor prognosis

Inhibiting ILT2 with Lenalidomide significantly activated NK cells and eliminated leukemic cells

[62]

Inhibition of PD-1 and TIM-3 receptors in circulating NK cells of 18 early-stage CLL patients did not affect the recovery of cytotoxic function and secretion of TNF-α and IFN-γ

[63]