Neutralization of (NK-cell-derived) B-cell activating factor by Belimumab restores sensitivity of chronic lymphoid leukemia cells to direct and Rituximab-induced NK lysis

Abstract

Natural killer (NK) cells are cytotoxic lymphocytes that substantially contribute to the therapeutic benefit of antitumor antibodies like Rituximab, a crucial component in the treatment of B-cell malignancies. In chronic lymphocytic leukemia (CLL), the ability of NK cells to lyse the malignant cells and to mediate antibody-dependent cellular cytotoxicity upon Fc receptor stimulation is compromised, but the underlying mechanisms are largely unclear. We report here that NK-cells activation-dependently produce the tumor necrosis factor family member 'B-cell activating factor' (BAFF) in soluble form with no detectable surface expression, also in response to Fc receptor triggering by therapeutic CD20-antibodies. BAFF in turn enhanced the metabolic activity of primary CLL cells and impaired direct and Rituximab-induced lysis of CLL cells without affecting NK reactivity per se. The neutralizing BAFF antibody Belimumab, which is approved for treatment of systemic lupus erythematosus, prevented the effects of BAFF on the metabolism of CLL cells and restored their susceptibility to direct and Rituximab-induced NK-cell killing in allogeneic and autologous experimental systems. Our findings unravel the involvement of BAFF in the resistance of CLL cells to NK-cell antitumor immunity and Rituximab treatment and point to a benefit of combinatory approaches employing BAFF-neutralizing drugs in B-cell malignancies.

NK cell function is markedly impaired in patients with chronic lymphocytic leukaemia but is preserved in patients with small lymphocytic lymphoma

“…Impaired cytolytic function of NK cells in patients with B-CLL has previously been described [13, 16, 25, 26]. This impairment has been attributed to a lack of azurophilic granules, impaired release of cytolytic molecules [13], and impaired expression of activating receptors [16].…”

Microenvironment interactions and B-cell receptor signaling in Chronic Lymphocytic Leukemia: Implications for disease pathogenesis and treatment

“…Human leukocyte antigen G (HLA-G) molecule overexpression in the plasma of CLL patients [78] induces NK-cell apoptosis and impairs NK-cell mediated cytotoxicity. Reduced NK-cell cytotoxicity has been associated to low expression levels of the activating receptors natural killer cell p30-related protein (NKp30) [79, 80] and natural killer group 2 member D (NKGD2) [81]; NK cells can also produce soluble BAFF, which interferes with NK-cell mediated CLL cell lysis after rituximab administration [82], and show reduced responses to the activating soluble BCL2-associated athanogene 6 (BAG6) ligand produced by CLL cells [79]. Taken together, these findings indicate that both the T and NK-cell compartments have overall reduced effector activities, which can explain the evasion of CLL cells from immune-mediated destruction.…”

“…The CD40/CD40L axis favors survival and proliferation of CLL cells [68, 101, 102], and interaction of PD-L1 ligand with PD-1, which is expressed at high levels on the surface of T cells from CLL patients, favors immune evasion of CLL cells from T-cell cytotoxicity [70, 72, 76]. Several factors contribute to reduced NK-cell cytotoxicity, including low expression of NK-cell activating receptors, such as NKp30 [79, 80], soluble BAFF release by NK cells [82], and soluble BAG6 release by CLL cells [77]. Adhesion to bone marrow stromal cells (BMSCs) is mediated by VCAM-1 or FN interaction with VLA-4 integrins [96], and chemotaxis towards BMSCs involves the CXCR4-CXCL12 axis [85].…”

NK cell dysfunction in chronic lymphocytic leukemia is associated with loss of the mature cells expressing inhibitory killer cell Ig-like receptors

“…28,29 Accordingly, lenalidomide is being tested in combination with rituximab to improve NK cell cytolytic and ADCC responses in CLL, and recent work suggests that the B-cell activating factor (BAFF) inhibitor, belimumab, may also be effective to improve rituximab efficacy. 11,[30][31][32] In view of the need for better understanding of the basis of NK cell defects in CLL patients, we performed a comprehensive prospective analysis of their status in previously untreated cohorts of adult patients with CLL or SLL, as compared with healthy controls of similar median age. Since NK cells are found more prevalently in peripheral blood than lymph nodes, we hypothesized that NK …”