Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
, 8 (10)

NK Cells in the Treatment of Hematological Malignancies


NK Cells in the Treatment of Hematological Malignancies

Ana P Gonzalez-Rodriguez et al. J Clin Med.


Natural killer (NK) cells have the innate ability to kill cancer cells, however, tumor cells may acquire the capability of evading the immune response, thereby leading to malignancies. Restoring or potentiation of this natural antitumor activity of NK cells has become a relevant therapeutic approach in cancer and, particularly, in hematological cancers. The use of tumor-specific antibodies that promote antibody-dependent cell-mediated cytotoxicity (ADCC) through the ligation of CD16 receptor on NK cells has become standard for many hematologic malignancies. Hematopoietic stem cell transplantation is another key therapeutic strategy that harnesses the alloreactivity of NK cells against cancer cells. This strategy may be refined by adoptive transfer of NK cells that may be previously expanded, activated, or redirected (chimeric antigen receptor (CAR)-NK cells) against cancer cells. The antitumor activity of NK cells can also be boosted by cytokines or immunostimulatory drugs such as lenalidomide or pomalidomide. Finally, targeting immunosubversive mechanisms developed by hematological cancers and, in particular, using antibodies that block NK cell inhibitory receptors and checkpoint proteins are novel promising therapeutic approaches in these malignant diseases.

Keywords: CAR-NK; NK cells; cancer; checkpoint; hematopoietic stem cell transplantation; immunotherapy.

Conflict of interest statement

The authors declare no conflicts of interest.


Figure 1
Figure 1
Natural killer (NK) cell activation: The activation of NK cells is mediated by a balance of signals provided by a network of activating and inhibitory receptors. Inhibitory receptors (depicted in red) recognize surface self-proteins normally expressed by all healthy nucleated cells. The loss of their expression, frequently caused by viral infection or cellular transformation, leads to NK cell activation (“missing self” recognition). Activating receptors (depicted in green) recognize ligands that are induced on virus-infected and malignant cells. Activated NK cells induce the apoptosis of tumor cells by the exocytosis of cytotoxic granules containing perforin and granzymes, and secrete cytokines, such as IFN-γ. Major inhibitory and activating receptors on NK cells and their cognate ligands on targets are depicted. IFN-γ, interferon-γ; TIGIT, T cell Ig and ITIM domain; PD-1, programmed death-1; iKIR, inhibitory killer cell immunoglobulin-like receptor; NKG2A, natural killer group 2A; NKG2D, natural killer group 2D; NKp30, natural killer P30; DNAM-1, DNAX accessory molecule 1; PVR, polivirus receptor; PD-L1 and 2, programmed death-ligand 1 and 2; MHC-I, MHC class I; HLA-E, human leucocyte antigen E; Ag, antigen; MICA, MHC class I polypeptide-related sequence A; MICB, MHC class I polypeptide-related sequence B; ULBP1-6, UL16 binding proteins 1–6.
Figure 2
Figure 2
Therapeutic approaches involving natural killer (NK) cells to treat hematological cancers. Cytotoxic mAbs that engage CD16 receptors on NK cells and induce antibody-dependent cell-mediated cytotoxicity (ADCC) are the most widely used NK cell-based therapies in hematological cancers. The so-called bispecific antibodies (BITE) may improve ADCC activity by redirecting NK cells to tumor cells. NK cells, and particularly allogenic NK cells that are devoid of inhibitory KIRs for donor´s HLA class I molecules, play a key role in the therapeutic efficacy of hematopoietic stem cell transplantation (HSCT). Alternatively, NK cells may be expanded, activated, or redirected against cancer cells (chimeric antigen receptor (CAR)-NK cells) ex vivo and adoptively transferred to patients with hematological cancers. The antitumor activity of NK cells may also be stimulated by cytokines or immunostimulatory drugs such as lenalidomide or pomalidomide. Due to their capability of stimulating NK cell activity and ADCC, they may have synergistic effects with therapeutic mAbs. Blocking antibodies directed against inhibitory NK cell receptors, including inhibitory KIRs (iKIR) (lirilumab) or natural killer group 2A (NKG2A) (monalizumab), and checkpoint proteins, including programmed death-1 (PD-1), have great clinical potential in this type of malignancies. Similarly, agonistic antibodies targeting T and NK cell costimulatory molecules, such as cluster of differentiation 137 (CD137)/4-1BB, are novel therapeutic alternatives for cancer therapy. HSC, hematopoietic stem cell; IMiDs, immunomodulatory drugs; mAbs, monoclonal antibodies. SLAMF7, SLAM family member 7.

Similar articles

See all similar articles


    1. Kiessling R., Klein E., Pross H., Wigzell H. “Natural” killer cells in the mouse. II. Cytotoxic cells with specificity for mouse Moloney leukemia cells. Characteristics of the killer cell. Eur. J. Immunol. 1975;5:117–121. doi: 10.1002/eji.1830050209. - DOI - PubMed
    1. Karre K., Ljunggren H.G., Piontek G., Kiessling R. Selective rejection of H-2-deficient lymphoma variants suggests alternative immune defence strategy. Nature. 1986;319:675–678. doi: 10.1038/319675a0. - DOI - PubMed
    1. Moretta L., Locatelli F., Pende D., Sivori S., Falco M., Bottino C., Mingari M.C., Moretta A. Human NK receptors: From the molecules to the therapy of high risk leukemias. FEBS Lett. 2011;585:1563–1567. doi: 10.1016/j.febslet.2011.04.061. - DOI - PubMed
    1. Sivori S., Vacca P., Del Zotto G., Munari E., Mingari M.C., Moretta L. Human NK cells: Surface receptors, inhibitory checkpoints, and translational applications. Cell. Mol. Immunol. 2019;16:430–441. doi: 10.1038/s41423-019-0206-4. - DOI - PMC - PubMed
    1. Sun J.C., Lanier L.L. NK cell development, homeostasis and function: Parallels with CD8(+) T cells. Nat. Rev. Immunol. 2011;11:645–657. doi: 10.1038/nri3044. - DOI - PMC - PubMed