Reactive oxygen species induced by therapeutic CD20 antibodies inhibit natural killer cell-mediated antibody-dependent cellular cytotoxicity against primary CLL cells

Werlenius, Olle; Aurelius, Johan; Hallner, Alexander; Akhiani, Ali A.; Simpanen, Maria; Martner, Anna; Andersson, Per‐Ola; Hellstrand, Kristoffer; Thorén, Fredrik B.

doi:10.18632/oncotarget.8769

Cited by 24 publications

(24 citation statements)

References 29 publications

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“…In line with our observation, there is already evidence about a robust extracellular release of ROS from neutrophils in CLL exposed to anti-CD20 treatment or αCD20-opsonized CLL cells [ 16 ]. The same authors proved that the enhanced ROS production by neutrophils and monocytes in CLL may limit the NK cell-mediated ADCC against CLL cells during anti-CD20 treatment, as NK cell ADCC could be partially restored by anti-oxidative agents [ 17 ]. Enhanced ROS production from neutrophils may also participate in tumorigenesis [ 18 ], induce mutations and genotoxicity generally [ 19 ], contribute to drug resistance and aggressive disease course [ 20 ] as well as to a systemic T- and NK-cell dysfunction [ 21 ].…”

Section: Discussionmentioning

confidence: 99%

Neutrophils in chronic lymphocytic leukemia are permanently activated and have functional defects

et al. 2017

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A growing body of studies highlights involvement of neutrophils in cancer development and progression. Our aim was to assess the phenotypic and functional properties of circulating neutrophils from patients with chronic lymphocytic leukemia (CLL). The percentage of CD54+ and CD64+ neutrophils as well as CD54 expression on these cells were higher in CLL patients than in age-matched healthy controls. Neutrophils from CLL produced more reactive oxygen species (ROS) compared to controls in both resting and activated conditions. Lipopolysaccharide-induced production of IL-1β and TNF-a as well as reduced TLR2 expression in neutrophils from CLL than in neutrophils from controls suggesting their tolerant state. Finally, phenotypic alterations of neutrophils, particularly elevation of CD64 and CD54 markers, correlated with disease activity and treatment, and low percentage of neutrophils. Taken together, the alterations in percentage and functional characteristics of neutrophils reflect the clinical course of CLL. Our data provide first evidence that neutrophils in CLL are permanently primed and have functional defects.

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Section: Discussionmentioning

confidence: 99%

Neutrophils in chronic lymphocytic leukemia are permanently activated and have functional defects

et al. 2017

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“…Preclinical and in vitro data indicate that complement activation, and in particular C3b deposition, inhibits rituximab-induced NK cell activation and ADCC 102–104 . Further, anti-CD20 mAbs have been implicated in the induction of ROS by monocytes with consequent inhibition of NK cell-mediated cytotoxicity 105 . In light of these findings, a better understanding of the precise mechanisms triggered by therapeutic mAbs in the context of different tumours is imperative to determining the optimal strategy for clinical manipulation of complement in cancer patients.…”

Section: Challenges Of Translational Researchmentioning

confidence: 99%

Complement in cancer: untangling an intricate relationship

et al. 2017

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In tumour immunology, complement has traditionally been considered as an adjunctive component that enhances the cytolytic effects of antibody-based immunotherapies, such as rituximab. Remarkably, research in the past decade has uncovered novel molecular mechanisms linking imbalanced complement activation in the tumour microenvironment with inflammation and suppression of antitumour immune responses. These findings have prompted new interest in manipulating the complement system for cancer therapy. This Review summarizes our current understanding of complement-mediated effector functions in the tumour microenvironment, focusing on how complement activation can act as a negative or positive regulator of tumorigenesis. It also offers insight into clinical aspects, including the feasibility of using complement biomarkers for cancer diagnosis and the use of complement inhibitors during cancer treatment.

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“…16,24,25 In addition, high expression levels of glucocorticoid-induced TNFR-related protein ligand (GITR) on CLL tumor cells and ROS production by monocytes can both reportedly reduce rituximab-mediated ADCC responses by NK cells. 26,27 Competent ADCC by NK cells can be important, since it has been shown to play a significant role in the therapeutic efficacy of certain antibodies, including rituximab in treating CLL and other B cell malignancies. 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.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2017

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A prospective analysis of natural killer (NK) cell phenotype and function was performed on fresh peripheral blood samples from untreated patients with B-cell chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Compared to healthy controls, CD56 dim NK cells in CLL patients displayed reduced expression of the NKG2D activating receptor and increased CD27 expression, which indicates declines in mature cells. In addition, NK cells from CLL patients showed reduced degranulation responses toward transformed B cells alone or with rituximab and were more sensitive to activation-induced cell death. We further noted a striking reduction in the frequency and viability of NK cells expressing the inhibitory killer cell Ig-like receptors (KIR)2DL1 and/or KIR3DL1, which progressed over time in most patients. Comparisons between a CLL patient and healthy monozygotic twin were consistent with our results in the larger cohorts. Functional and biomarker alterations were less pronounced on NK cells from SLL patients, which have lower tumor burden in peripheral blood than CLL, but significant reduction in degranulation under ADCC conditions and lower frequency and viability of KIR-expressing NK cells were still evident in SLL. We conclude that mature KIR-expressing NK cells respond to the high circulating B cell tumor burden in CLL, but undergo activation-induced apoptosis. Consequently, CLL patients may benefit from therapies that augment NK cell survival and function.

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Reactive oxygen species induced by therapeutic CD20 antibodies inhibit natural killer cell-mediated antibody-dependent cellular cytotoxicity against primary CLL cells

Cited by 24 publications

References 29 publications

Neutrophils in chronic lymphocytic leukemia are permanently activated and have functional defects

Neutrophils in chronic lymphocytic leukemia are permanently activated and have functional defects

Complement in cancer: untangling an intricate relationship

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

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