NK cell defects: implication in acute myeloid leukemia

Abstract

Acute Myeloid Leukemia (AML) is a complex disease with rapid progression and poor/unsatisfactory outcomes. In the past few years, the focus has been on developing newer therapies for AML; however, relapse remains a significant problem. Natural Killer cells have strong anti-tumor potential against AML. This NK-mediated cytotoxicity is often restricted by cellular defects caused by disease-associated mechanisms, which can lead to disease progression. A stark feature of AML is the low/no expression of the cognate HLA ligands for the activating KIR receptors, due to which these tumor cells evade NK-mediated lysis. Recently, different Natural Killer cell therapies have been implicated in treating AML, such as the adoptive NK cell transfer, Chimeric antigen receptor-modified NK (CAR-NK) cell therapy, antibodies, cytokine, and drug treatment. However, the data available is scarce, and the outcomes vary between different transplant settings and different types of leukemia. Moreover, remission achieved by some of these therapies is only for a short time. In this mini-review, we will discuss the role of NK cell defects in AML progression, particularly the expression of different cell surface markers, the available NK cell therapies, and the results from various preclinical and clinical trials.

Keywords: AML; BiKEs; CAR-NK; TriKEs; immunotherapy; natural killer cells.

Figure 1

Mechanisms of tumor cell escape in AML due to NK cell defects. AML cells can evade tumor surveillance due to various defects in the NK cell that lead to reduced NK cell cytotoxicity: 1) Reduced density of natural cytotoxicity receptors (NCRs) on NK cell surface leading to a NCR^dull phenotype with lower cytolytic activity. 2) Overexpression of inhibitory Killer immunoglobulin like receptors resulting in higher inhibition of cytotoxicity. 3) Defective maturation of NK cells with majority cells with hypomature profile expressing CD56^bright/dim KIRs^- CD57^-. 4) Expression of checkpoint inhibitors like PD-1 and TIGIT resulting in cells with reduced proliferative potential and lower cytotoxic and cytokine-producing capabilities. (Figure created in BioRender).

Figure 2

NK cell based immunotherapies. 1) Adoptive NK cell therapy. Infusion of cytokine stimulated ex vivo expanded donor derived NK cells 2) Infusion of CAR-NK construct that comprises an extracellular receptor recognizing a specific antigen, a hinge region, and a transmembrane domain and intracellular co-stimulatory domains. 3) NK cell engagers consisting of bi-specific killer engagers (BiKEs) and tri-specific killer engagers (TriKEs), comprised of a single variable antibody portion (V_H and V_L) that links to either one (BiKE) or two (TriKE) variable portions on other antibodies. 4) Immune checkpoint proteins when bound to their ligands suppress NK cell activity facilitating tumor evasion. Blocking these checkpoint proteins with inhibitors prevents NK suppression (Figure created in BioRender).