Deficiency of natural killer cell activity in patients with chronic lymphocytic leukemia

Abstract

Natural killer (NK)6 cell activity of peripheral blood lymphocytes against human leukemia cell lines was measured in patients with chronic B-cell lymphocytic leukemia (CLL) and age- and sex-matched controls. In order to remove the leukemia cells that interfere with the in vitro assay we (1) isolated lymphocytes that form rosettes with sheep red blood cells (SRBC) or (2) lysed the CLL cells with a monoclonal anti-B cell antibody and complement. NK activity in either lymphocyte preparation from nine of 10 patients with advanced disease was not detectable and, when calculated in terms of lytic units per ml of blood, as at least seven times lower than in controls; only one of these patients exhibited activity within the control range. Two patients with early disease had measurable, but low, NK-cell activity. Prolongation of the NK cell assay from 6 to 18h gave rise to significant killing in the CLL patients lacking NK cell activity in the 6-h assay; however, the activity still was six times lower than in controls. Treatment of leukemia cell-depleted lymphocytes from CLL patients with human fibroblast interferon or the interfeon inducer poly 1:C enhanced NK-cell activity in the two early stage patients but this treatment was ineffective in three later stage patients. The percentage of cells with characteristics of NK cells, i.e. those with receptors for SRBC and Fc-portion of IgG, was four times higher in CLL patients and the percentage of lymphocytes binding to NK-sensitive target cells was equal to that in controls despite the fact that, in the majority of patients, lysis of the target cells by the lymphocytes does not ensue. The NK deficiency may be responsible for the increased incidence of secondary malignancies in CLL patients.

Analysis of CD16+CD56dim NK cells from CLL patients: evidence supporting a therapeutic strategy with optimized anti-CD20 monoclonal antibodies

“…Poor expression of CD69 was also observed on CD16 þ CD56 dim NK cells from CLL patients; this deficit could explain the previously reported reduction in NK cytotoxic activity in the absence of exogenous stimulation. 15,28 This relative NK-cell anergy could be due to the ability of CLL cells and their microenvironment to produce cytokines, such as IL-10, which suppress the proliferation of antigen-specific Th1 cells and downregulate co-stimulatory molecules on antigen-presenting cells. [29][30][31] Importantly, NK-cell function was perfectly recovered following activation.…”

“…14 Several studies have reported functional alterations in NK cells in these patients, including defective cytotoxic activity, which are particularly pronounced in advanced disease and that could be because of the accumulation of leukemic cells rather than to any intrinsic defect in the former. 15,16 This hypothesis was suggested by the restoration of their functional activity after interferon (IFN)-a and/or interleukin (IL)-2 treatment. 17,18 We conducted the first extensive characterization of the phenotypic and cytotoxic qualities of NK cells from CLL patients and compared them with those of healthy subjects.…”

Expansion of natural killer (NK) and natural killer-like T (NKT)-cell populations derived from patients with B-chronic lymphocytic leukemia (B-CLL): a potential source for cellular immunotherapy

“…Rather, triggering of NK cell cytotoxicity reflects a balance between activating and inhibitory signals mediated by cell-surface receptors that belong to several different gene families. [12][13][14][15] In B-CLL patients, several phenotypic and functional alterations in NK cells 16,17 have been described such as defective cytotoxic activity. [16][17][18][19] The reason as to why NK activity is low in most patients with CLL is unclear.…”

Glycovariant anti-CD37 monospecific protein therapeutic exhibits enhanced effector cell-mediated cytotoxicity against chronic and acute B cell malignancies

“…The NK cell activity was not detectable in patients with advanced disease and six times lower than control in patients with early disease. 28 This finding, however, has been challenged by others. 29 To test whether CLL NK cells would be capable of mediating an effective response with SMIP-016 GV , we used NK cells from patients with early stage disease as effectors in ADCC assays against Raji cells targets.…”