DNA damage response and evasion from immunosurveillance in CLL: new options for NK cell-based immunotherapies

Abstract

Chronic lymphocytic leukemia (CLL) is the most prominent B cell malignancy among adults in the Western world and characterized by a clonal expansion of B cells. The patients suffer from severe immune defects resulting in increased susceptibility to infections and failure to generate an antitumor immune response. Defects in both, DNA damage response (DDR) pathway and crosstalk with the tissue microenvironment have been reported to play a crucial role for the survival of CLL cells, therapy resistance and impaired immune response. To this end, major advances over the past years have highlighted several T cell immune evasion mechanisms in CLL. Here, we discuss the consequences of an impaired DDR pathway for detection and elimination of CLL cells by natural killer (NK) cells. NK cells are considered to be a major component of the immunosurveillance in leukemia but NK cell activity is impaired in CLL. Restoration of NK cell activity using immunoligands and immunoconstructs in combination with the conventional chemotherapy may provide a future perspective for CLL treatment.

Keywords: DNA damage response; chronic lymphocytic leukemia; immunoconstructs; immunoligands; immunotherapy; natural killer cell.

FIGURE 1

Figure 1. A hypothetical model of CLL escape from NK response. The left panel of the figure demonstrate general mechanism of the escape from NK-cell response by CLL cells. The escape of CLL cells from the NK cell response is regulated at different levels; (1) diminished expression NKG2D ligands on the cell surface, (2) increased levels of ligands for inhibitory receptors ILT2 and NKG2A/B, (3) shedding by MMPs and production of soluble ligands for activating receptors (ULBP2, MICA, and BAG6) NKG2D and NKp30 (Iclozan et al., 2013), which rather suppress than activate NK cells. Indirect suppression of NK cell activity might be regulated by MDSC and Treg cells via production of TGFβ and IL-10, which modulate expression levels of activating receptors on the cell surface of NK cells. The right panel of the figure is focused on the impaired DDR and its role for the escape from NK-cell response. Induction of DDR in healthy cells results in activation ATM-p53 axis. Activation of p53 results in cell surface expression of NKG2D ligands and exosomal release of BAG6 following transcriptional activation of TSAP6. Cell surface expression of NKG2D ligands and exosomal expression of BAG6 is impaired in CLL cells due to defects in DDR.

FIGURE 2

Figure 2. Potential role of immunoligands to redirect NK cells to CLL cells. Immunoligands with specificities for CLL cells (through CD19 or CD20) and for NK cells [through activating receptors on NK cells such as NKG2D, NKp30, FcγRIIIa or simultaneous NKp30 and FcγRIIIa(1–4)] can link and activate respective immune cells even in the presence of active immune suppression. Stimulating of either of the activating receptors on NK cell leads to cytokine secretion (IFNγ, TNFα) and degranulation, thereby killing tumor cells by apoptosis. Professional antigen presenting cells (APCs) such as dendritic cells (DCs) phagocytose components of dying tumor cells and present tumor antigens to both CD8⁺ and CD4⁺ T cells, thereby inducing cell-mediated and humoral adaptive immunity and memory response. Direct NK–DC crosstalk in terms of maturation of DCs and killing of immature DCs is mainly attributed to NKG2D and NKp30 activation. Additionally, following activation NK cells express OX40 ligand (OX40L) and CD86 on the cell surface, which can bind to the co-stimulatory receptors OX40 and CD28 expressed by CD4⁺ T cells. Direct interaction between NK and CD4⁺ T cells through such co-stimulatory molecules can enhance T cell effector functions.