Natural Killer Cells in Chronic Lymphocytic Leukemia: Functional Impairment and Therapeutic Potential

Abstract

Immunotherapy approaches have advanced rapidly in recent years. While the greatest therapeutic advances so far have been achieved with T cell therapies such as immune checkpoint blockade and CAR-T, recent advances in NK cell therapy have highlighted the therapeutic potential of these cells. Chronic lymphocytic leukemia (CLL), the most prevalent form of leukemia in Western countries, is a very immunosuppressive disease but still shows significant potential as a target of immunotherapy, including NK-based therapies. In addition to their antileukemia potential, NK cells are important immune effectors in the response to infections, which represent a major clinical concern for CLL patients. Here, we review the interactions between NK cells and CLL, describing functional changes and mechanisms of CLL-induced NK suppression, interactions with current therapeutic options, and the potential for therapeutic benefit using NK cell therapies.

Cutaneous malignancies in chronic lymphocytic leukemia

“…CLL‐related changes in the adaptive immune system are broadly characterized as defects in the humoral immune system as a result of hypogammaglobulinemia, increased production of the immunosuppressive cytokine interleukin (IL)‐10, increased numbers of T regulatory cells, reversal of the normal CD4:CD8 T cell ratio, alterations in T cell function, and higher numbers of CD4 + and CD8 + cells expressing immune checkpoint receptors 81–84 . Changes in the innate immune system that result in an acquired immunosuppressed state also include the production of defective macrophages, dendritic cells, natural killer (NK) cells, and neutrophils, and alterations in the level and function of complement 85–88 …”

“…[81][82][83][84] Changes in the innate immune system that result in an acquired immunosuppressed state also include the production of defective macrophages, dendritic cells, natural killer (NK) cells, and neutrophils, and alterations in the level and function of complement. [85][86][87][88] In a large retrospective cohort study by Parikh et al, 25% of newly diagnosed CLL patients had hypogammaglobulinemia 81 and another 25% developed hypogammaglobulinemia over the subsequent 10 years. 81 Correlation between hypogammaglobulinemia and OS was not demonstrated.…”

“…85 There are also changes to the NK cell population, which is expanded in number but demonstrates dysfunctional and altered behavior, including reduced expression of activating receptors NKG2D, DNAM-1, NKp30, and NKp46, decreased production of cytolytic molecules following stimulation, and downregulation of other genes (i.e., cell adhesion molecules) involved in cytotoxicity. 88,[99][100][101] Levels of complement components C1-4 are reduced. 87 Peripheral blood neutrophils in CLL patients express higher levels of the activation markers CD54 and CD64.…”

Assessment of Impact of Human Leukocyte Antigen-Type and Cytokine-Type Responses on Outcomes after Targeted Therapy Currently Used to Treat Chronic Lymphocytic Leukemia

“…Verheyden et al conducted a study that revealed the downregulation of HLA-A, -B, and -C alleles in CLL cells [ 51 ]. Moreover, several studies have indicated that there is a defective cytolytic function of NK cells in CLL, although no differences in natural cytotoxicity receptor expression were observed between CLL patients and healthy age-matched individuals [ 53 , 54 ]. Nevertheless, a clinical data analysis revealed that reduced natural cytotoxicity receptor expression was linked to specific factors, including low hemoglobin levels and elevated lymphocyte counts [ 55 ].…”

Cellular Therapy in Chronic Lymphocytic Leukemia: Have We Advanced in the Last Decade?

“…At the same time, other groups failed to demonstrate such an effect of either autologous or allogeneic NK cells [90, 91]. Similar to T cells (although with less robust data), NK cells derived from CLL patients exhibit impaired function, expressed by decreased cytotoxicity, downregulation of NK activating receptors, and upregulation of inhibitory receptors [92]. One of the main advantages of using NK cells compared to T cells is the reduced risk of GvHD [93], enabling the use of an “off-the-shelf product” with no need for HLA matching and/or genetic modification (as is the case with allogeneic T cells).…”