Immunomodulatory Activity of Tyrosine Kinase Inhibitors to Elicit Cytotoxicity Against Cancer and Viral Infection

Abstract

Tyrosine kinase inhibitors (TKIs) of aberrant tyrosine kinase (TK) activity have been widely used to treat chronic myeloid leukemia (CML) for decades in clinic. An area of growing interest is the reported ability of TKIs to induce immunomodulatory effects with anti-tumor and anti-viral activity, which appears to be mediated by directly or indirectly acting on immune cells. In selected cases of patients with CML, TKI treatment may be interrupted and a non-drug remission may be observed. In these patients, an immune mechanism of increased anti-tumor cytotoxic activity induced by chronic administration of TKIs has been suggested. TKIs increase some populations of natural killer (NK), NK-LGL, and T-LGLs cells especially in dasatinib treated CML patients infected with cytomegalovirus (CMV). In addition, dasatinib increases responses against CMV and is able to inhibit HIV replication in vitro. Recent studies suggest that subclinical reactivation of CMV could drive expansion of specific subsets of NK- and T-cells with both anti-tumoral and anti-viral function. Therefore, the underlying mechanisms implicated in the expansion of this increased anti-tumor and anti-viral cytotoxic activity induced by TKIs could be a new therapeutic approach to take into account against cancer and viral infections such as HIV-1 infection. The present review will briefly summarize the immunomodulatory effects of TKIs on T cells, NKs, and B cells. Therapeutic implications for modulating immunity against cancer and viral infections and critical open questions are also discussed.

Keywords: SAMHD1; T cells; adaptive natural killer cells; chronic myeloid leukemia; cytomegalovirus; dasatinib; human immunodeficiency virus; tyrosine kinase inhibitors.

Figure 1

Model showing the potential mechanisms that drive NK cell and CD8⁺ T cell expansion in CMV seropositive dasatinib-treated patients with CML. (1) Before dasatinib-treatment, CMV-latent infected cells underwent a low level of CMV reactivation in CML patients. Some NK cells are immature NK cells (NKG2A⁺ NKG2C^-NKp30^highNKp46^high) and a small number of CMV-associated NKG2C⁺ CD57⁺NK cells and memory CD8⁺ T-cells have been generated. However, a high amount of suppressor cells, such as Tregs and M-MDSC, is found. (2) Dasatinib in vivo leads to cycles of immunosuppression, which enhance subclinical reactivation of CMV and provide a replicative niche for CMV-specific memory NK cells and memory CD8⁺ T-cells. On the other hand, dasatinib treatment reduces immature NK cells load and suppressor cells amount. (3) These reduced suppressor cell load potentiates a larger expansion and effector function of CMV-specific memory NK cells and memory CD8⁺ T-cells. (4) These cells are recognized as LGLs and mediated cytotoxic activity against CMV improving disease outcomes as a consequence of CML-associated antigen cross-recognition. Adapted from Kadowaki et al. (2017).

Figure 2

Schematic representation of dasatinib mediated mechanisms that could interfere with HIV-1 infection. (1) Inhibition of SAMHD1 phosphorylation, maintaining its intrinsic antiviral activity; (2) inhibition of mass activation, establishment of viral reservoirs, depletion of CD4⁺ T cells, and reduction of infected cells that carry the pro-viral DNA of HIV-1; (3) inhibition of inflammation and reduction in senescence; (4) potentiation of cytotoxic activity mediated by memory NK cells and T lymphocytes against HIV; (5) increase of immune effector cells such as cytotoxic LGLs by reducing levels of Tregs and M-MDSC, which are suppressor cells. Adapted from Coiras et al. (2017).