Resistance of Chronic Lymphocytic Leukaemia Cells to Interferon-α Generated Lymphokine Activated Killer Cells

Abstract

Recent studies have shown that, when used in early stage disease, interferon-alpha (IFN-alpha) can produce a fall in the number of malignant cells in the peripheral blood of patients with B-CLL. In this study, we investigated the effect of IFN-alpha on natural killer (NK) cell and lymphokine-activated cell (LAK) activity in patients with B-CLL. In vitro, IFN-alpha (500 U/ml for 18 hours) induced LAK activity in patients with B-CLL (27.7 +/- 9.9%, n = 20), and IL-2 (500 U/ml for 5 days) produced similar activity (35.9 +/- 8.8%, n = 7). Despite the induction of LAK activity by IFN-alpha and IL2 in patients with B-CLL, the malignant cells remained resistant to both allogeneic and autologous LAK effectors. NK activity in patients with B-CLL is also low (23.1 +/- 7.2%, n = 20), and B-CLL cells were resistant to NK cell activity. In cold target competition assays, CLL cells did not compete with labelled K562 or Daudi targets in the NK and LAK assays, suggesting that the malignant cells are not recognised by the effector cells, and this may be related to low level of expression of the adhesion receptors, LFA-1 and ICAM-1. Finally, CLL cells were also resistant to antibody dependent cell mediated cytotoxicity, but were susceptible to antibody dependent complement mediated lysis. These results suggest that it is unlikely that the effects of IFN-alpha in B-CLL are due to the enhancement of NK or LAK activity.

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.…”

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

“…29 The observation that NK activity is significantly reduced in peripheral blood of CLL patients as compared to healthy donors could argue for an NK cell dysfunction contributing to tumor cell accumulation in vivo. [16][17][18][19] Reasonably, then, increased numbers and/or activity of killer cells might be therapeutically beneficial for CLL, as it has been shown that NK cells have low cytotoxic capacity in B-CLL patients. [16][17][18][19] However, with all leukemic patients, autologous antileukemic effector cells are difficult to collect because of their limited number in the peripheral blood.…”

“…[16][17][18][19] Reasonably, then, increased numbers and/or activity of killer cells might be therapeutically beneficial for CLL, as it has been shown that NK cells have low cytotoxic capacity in B-CLL patients. [16][17][18][19] However, with all leukemic patients, autologous antileukemic effector cells are difficult to collect because of their limited number in the peripheral blood. Previously, others studied expansion of NKT but not of NK cells from the peripheral blood of B-CLL patients.…”

“…In as much as CD16 is an Fc receptor involved in ADCC, [16][17][18] the expanded cell populations generated here could be instrumental as effectors following Mab therapy. The Mab, Campath-1H, had only a marginal effect on CD16 þ NK cells compared to that on T and B cells, 35 but deficiency in the number of NK and NKT cells remains several months after Campath-1H therapy (personal communication).…”

“…[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. A dilutional effect of leukemic cells and intrinsic functional defects on NK cells have been implicated.…”