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Review
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Natural Killer Cells in Myeloid Malignancies: Immune Surveillance, NK Cell Dysfunction, and Pharmacological Opportunities to Bolster the Endogenous NK Cells

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Review

Natural Killer Cells in Myeloid Malignancies: Immune Surveillance, NK Cell Dysfunction, and Pharmacological Opportunities to Bolster the Endogenous NK Cells

Mattias Carlsten et al. Front Immunol.

Abstract

Natural killer (NK) cells are large granular lymphocytes involved in our defense against certain virus-infected and malignant cells. In contrast to T cells, NK cells elicit rapid anti-tumor responses based on signals from activating and inhibitory cell surface receptors. They also lyse target cells via antibody-dependent cellular cytotoxicity, a critical mode of action of several therapeutic antibodies used to treat cancer. A body of evidence shows that NK cells can exhibit potent anti-tumor activity against chronic myeloid leukemia (CML), acute myeloid leukemia (AML), and myelodysplastic syndromes (MDS). However, disease-associated mechanisms often restrain the proper functions of endogenous NK cells, leading to inadequate tumor control and risk for disease progression. Although allogeneic NK cells can prevent leukemia relapse in certain settings of stem cell transplantation, not all patients are eligible for this type of therapy. Moreover, remissions induced by adoptively infused NK cells are only transient and require subsequent therapy to maintain durable responses. Hence, new strategies are needed to trigger full and durable anti-leukemia responses by NK cells in patients with myeloid malignancies. To achieve this, we need to better understand the interplay between the malignant cells, their microenvironment, and the NK cells. This review focuses on mechanisms that are involved in suppressing NK cells in patients with myeloid leukemia and MDS, and means to restore their full anti-tumor potential. It also discusses novel molecular targets and approaches, such as bi- and tri-specific antibodies and immune checkpoint inhibitors, to redirect and/or unleash the NK cells against the leukemic cells.

Keywords: NK cell dysfunction; NK cells; cancer immunotherapy; drug development; myeloid malignancy.

Figures

Figure 1
Figure 1
NK cell receptors, their function, and ligands. Schematic illustration showing how NK cell activity and cytotoxicity are controlled by signals from cell surface receptors. Cytokines and corresponding cytokine receptors on the NK cell are shown at the lower part of the NK cell. Inhibitory signals triggered by receptors (red) upon engagement of their ligands (in brackets) are shown on the left side of the NK cell. Activating signals triggered by receptors (green) upon engagement of their ligands (in brackets) are shown on the right side. Binding of LFA-1 (blue) on NK cells to ICAM-1 on target cells direct the granulae release toward the target cell, which is needed for efficient target cell lysis.
Figure 2
Figure 2
Mechanisms behind NK cell dysfunction and phenotypic/maturation alterations in myeloid malignancies. Schematic illustration showing how various mechanisms contribute to NK cell dysfunction and phenotypic/maturation alterations. (A) NK cells arise from hematopoietic stem cells (HSCs) that through progenitor stages differentiate to mature NK cells (purple). Initiating genetic aberrations in myeloid malignancies are thought to arise in HSCs, referred to as pre-malignant HSCs, that among other cell types give rise to NK cells, which are dysfunctional in their cytotoxic capacity and have altered maturation. (B) NK cells are regulated by various secreted factors and cell–cell interactions affecting their cytotoxic and cytokine-secreting capacity. Regulatory T cells (Tregs), myelo-derived suppressor cells (MDSC), and malignant myeloid cells contribute to the suppression of NK cells that become dysfunctional with altered cytokine secretion and reduced cytotoxic capacity.
Figure 3
Figure 3
Drugs and approaches explored to restore and augment the antileukemia-capacity of NK cells. Schematic illustration showing how drugs can restore, augment, and direct NK cell-mediated killing of malignant myeloid cells. Drugs promoting NK cell-mediated killing of myeloid malignant cells by directly affecting NK cells, inhibiting regulatory T cells (Tregs) or myelo-derived suppressor cells (MDSC), and/or affecting malignant myeloid cells are shown. IL-2DT, IL-2 diphtheria toxin fusion protein. IMiDs, immunomodulatory imide drugs (include thalidomide and analogs such as lenalidomide and pomalidomide). AHRi, aryl hydrocarbon receptor inhibitor; GSK3βi, GSK3β inhibitor; HMA, hypomethylating agents (includes azacytidine and decitabine).

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References

    1. Herberman RB, Nunn ME, Lavrin DH. Natural cytotoxic reactivity of mouse lymphoid cells against syngeneic acid allogeneic tumors. I. Distribution of reactivity and specificity. Int J Cancer. (1975) 16:216–29. 10.1002/ijc.2910160204 - DOI - PubMed
    1. Herberman RB, Nunn ME, Holden HT, Lavrin DH. Natural cytotoxic reactivity of mouse lymphoid cells against syngeneic and allogeneic tumors. II. Characterization of effector cells. Int J Cancer. (1975) 16:230–9. 10.1002/ijc.2910160205 - DOI - PubMed
    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) 5:117–21. 10.1002/eji.1830050209 - DOI - PubMed
    1. Kiessling R, Klein E, Wigzell H. Natural killer cells in the mouse. I. Cytotoxic cells with specificity for mouse Moloney leukemia cells. Specificity and distribution according to genotype. Eur J Immunol. (1975) 5:112–7. 10.1002/eji.1830050208 - DOI - PubMed
    1. O'Sullivan TE, Sun JC, Lanier LL. Natural killer cell memory. Immunity. (2015) 43:634–45. 10.1016/j.immuni.2015.09.013 - DOI - PMC - PubMed
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