NK cell-based immunotherapy strategies for myeloid leukemia

Abstract

Myeloid leukemia (ML) is a clonal malignant disease with abnormal hematopoietic stem cells. With the emergence of novel immunotherapies, such as CAR-T, therapeutic outcomes in ML patients have improved, while significant challenges persist, including severe adverse events and disease recurrence. Natural killer cells (NK cells) are "natural killers" of the immune system that do not require antigen presentation and responsible for recognizing and destroying tumor cells. Some NK cells-based clinical experiments have been carried out and achieved remarkable results with lower side effects in ML. Crucially, within the ML microenvironment, NK cells frequently exhibit more severe functional exhaustion compared with T cells, characterized by impaired cytotoxicity, cytokine production, and proliferative capacity which limits anti-ML efficacy of NK cells. However, clinical studies utilizing NK cell-based therapies (e.g., adoptive transfer, CAR-NK cells) have demonstrated promising results with favorable safety profiles, underscoring their therapeutic potential. Therefore, developing more strategies based on NK cell is of great clinical significance for the treatment of ML. In this review, we systematically analysed the relationship between ML and NK cells, aiming to propose more novel protocols for NK cell expansion and persistence enhancement, establish evidence-based guidelines for next-generation NK cell-based immunotherapies in ML treatment.

Keywords: NK cell; exhaustion; immunobiology; myeloid leukemia; therapeutic potential.

Figure 1

Crosstalk between NK cells and TME. (a) NK cells develop from HSCs in BM, with down-regulation of CXCR4 expression, upregulation of CXCR3 expression, NK cells mature and enter PB and tissues. (b) After exudation from PB, NK cells are recruited to TME by integrins, chemokine receptors and selectins, and secrete cytokines or chemokines to recruit other immune cells and improve anti-tumor response through degranulation, ADCC or FASL/TRAIL induced tumor cell apoptosis. (c) NK cell function is often inhibited by suppressors secreted by tumor cells and DCs or by direct interaction with CD4⁺ T cells. In addition, NK cells can also secrete angiogenic factors to promote tumor angiogenesis.

Figure 2

NK cells in AML. (a) NK cells exhibited impaired killing ability and exhausted phenotype. CD3^-CD56⁺ NK cells in AML was decreased and Tregs or BMSCs secreting IL-10 or TGF-β also contributed to NK cell exhaustion in AML. (b) Decitabine could upregulating LFA expression on NK cells and inducing ICAM-1 expression on AML cells, thereby enhancing the cytotoxic activity of AML-NK cells. CD34⁺ NK cells, CD56⁺ NK cells or CIML-NK cells could directly kill AML cells. CD33/CD123/CD267 CAR-NK cells and TriKE molecules targeting CLEC12A were also used to reactive NK cells for killing AML cells and LSCs. Immune escape of NK cells is caused by residual LSCs and binding of PD-L1 on the surface of AML cells to PD-1 on the surface of NK cells, which results in AML recurrence.

Figure 3

NK cells in CML. (a) Immune cell subpopulations and CML cells secreted IL-10 or TGF-β which contributed to dysfunction of NK cells. Meanwhile, Mature CD56^dimCD16/57^bright NK cells and circulating NK cells were reduced which could promote CML occurence and recrudescence. (b) NK cells could demonstrate direct cytotoxicity against CML cells and both CD56⁺CD3^- NK cells and CD56⁺CD3⁺ NK-T cells suppress proliferation of BCR-ABL⁺ progenitors through JAK-2/STAT-5 pathway activation. To enhance NK cell expansion and cytotoxicity, PBMCs cells were treated with IL-15 and 41-BB could increase the number of CD56⁺CD3⁺ NK cells, CD25 CAR-NK92 cells can effectively kill CML cells. In reversing TKIs resistance, CML-RAE-1γ-Dex activate both NK cells and T lymphocytes, and inhibit the proliferation of TKIs-resistant CML cells.