Immunomodulatory Activity of the Tyrosine Kinase Inhibitor Dasatinib to Elicit NK Cytotoxicity against Cancer, HIV Infection and Aging

Abstract

Tyrosine kinase inhibitors (TKIs) have been extensively used as a treatment for chronic myeloid leukemia (CML). Dasatinib is a broad-spectrum TKI with off-target effects that give it an immunomodulatory capacity resulting in increased innate immune responses against cancerous cells and viral infected cells. Several studies reported that dasatinib expanded memory-like natural killer (NK) cells and γδ T cells that have been related with increased control of CML after treatment withdrawal. In the HIV infection setting, these innate cells are associated with virus control and protection, suggesting that dasatinib could have a potential role in improving both the CML and HIV outcomes. Moreover, dasatinib could also directly induce apoptosis of senescence cells, being a new potential senolytic drug. Here, we review in depth the current knowledge of virological and immunogenetic factors associated with the development of powerful cytotoxic responses associated with this drug. Besides, we will discuss the potential therapeutic role against CML, HIV infection and aging.

Keywords: CML; CMV; HIV functional cure; HIV-1; anti-aging; cancer; dasatinib; memory-like NK cells; senolytic; tyrosine kinase inhibitors; γδ T cells.

Figure 1

Scheme of dasatinib-mediated effects that may interfere with chronic myeloid leukemia (CML), HIV-1 infection and cellular senescence. (A) CML cell killing by the enhancement of memory natural killer (NK) cells and cytotoxic CD8⁺ T cells expressing γδTCR and a reduction of inhibitory receptors driven by dasatinib. (B) HIV infected cells’ clearance, carrying pro-viral DNA, by dasatinib activity through the potentiation of the above cell subpopulations. (C) Representation of both direct killing and a potential indirect effect by boosting NK and CD8⁺ cells of senescent cells with dasatinib. Figure made with BioRender.com (accessed on 7 March 2023).

Figure 2

(A) Representation of NK cell inhibitory and activating receptor-ligand pairs. Adapted from [9]. Figure made with BioRender.com. (B) NK cell education process and “missing self” killing of target cells. (a) NK cells are recognized through KIR3DL1 receptor host cells expressing HLA-Bw4 and become educated to recognize its absence then in target cells. This process leads to an efficient target cell killing. (b) Absence of recognition of HLA-Bw4 by KIR3DL1 drives a deficient cell killing of target cells with “missing self” by miseducation of the NK cell. Adapted from [12]. Figure made with BioRender.com. (C) Genomic organization of KIR A and B haplotypes. Adapted from [12].

Figure 2

(A) Representation of NK cell inhibitory and activating receptor-ligand pairs. Adapted from [9]. Figure made with BioRender.com. (B) NK cell education process and “missing self” killing of target cells. (a) NK cells are recognized through KIR3DL1 receptor host cells expressing HLA-Bw4 and become educated to recognize its absence then in target cells. This process leads to an efficient target cell killing. (b) Absence of recognition of HLA-Bw4 by KIR3DL1 drives a deficient cell killing of target cells with “missing self” by miseducation of the NK cell. Adapted from [12]. Figure made with BioRender.com. (C) Genomic organization of KIR A and B haplotypes. Adapted from [12].

Figure 3

NK cell education outline in HIV context by KIR3DL1/HLA-Bw4, associated with HIV infection control. Adapted from [9]. Figure made with BioRender.com.