Rituximab induces phenotypical and functional changes of NK cells in a non-malignant experimental setting

Merkt, Wolfgang; Lorenz, Hanns‐Martin; Watzl, Carsten

doi:10.1186/s13075-016-1101-3

Cited by 22 publications

(30 citation statements)

References 33 publications

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“…Furthermore, the glyco-engineered Obinutuzumab appears to be less affected by the inhibitory effects of KIR/HLA ligation compared to Rituximab (220). Several lines of evidence, from in-vitro and animal studies show that NK cells are involved in the mechanism of action of Rituximab/ Obinutuzumab (221)(222)(223)(224), yet their exact role in clinical settings are not completely understood. A recent clinical study suggested that lower peripheral NK cell counts in follicular lymphoma and lower peripheral and tumor infiltrated NK cell numbers in diffuse large B-cell lymphoma associate with transient progression-free survival in response to therapy (225).…”

Section: Nct02240706 Nct02632721mentioning

confidence: 99%

Unleashing Natural Killer Cells in the Tumor Microenvironment–The Next Generation of Immunotherapy?

2020

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The emergence of immunotherapy for cancer treatment bears considerable clinical promise. Nevertheless, many patients remain unresponsive, acquire resistance, or suffer dose-limiting toxicities. Immune-editing of tumors assists their escape from the immune system, and the tumor microenvironment (TME) induces immune suppression through multiple mechanisms. Immunotherapy aims to bolster the activity of immune cells against cancer by targeting these suppressive immunomodulatory processes. Natural Killer (NK) cells are a heterogeneous subset of immune cells, which express a diverse array of activating and inhibitory germline-encoded receptors, and are thus capable of directly targeting and killing cancer cells without the need for MHC specificity. Furthermore, they play a critical role in triggering the adaptive immune response. Enhancing the function of NK cells in the context of cancer is therefore a promising avenue for immunotherapy. Different NK-based therapies have been evaluated in clinical trials, and some have demonstrated clinical benefits, especially in the context of hematological malignancies. Solid tumors remain much more difficult to treat, and the time point and means of intervention of current NK-based treatments still require optimization to achieve long term effects. Here, we review recently described mechanisms of cancer evasion from NK cell immune surveillance, and the therapeutic approaches that aim to potentiate NK function. Specific focus is placed on the use of specialized monoclonal antibodies against moieties on the cancer cell, or on both the tumor and the NK cell. In addition, we highlight newly identified mechanisms that inhibit NK cell activity in the TME, and describe how biochemical modifications of the TME can synergize with current treatments and increase susceptibility to NK cell activity.

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Section: Nct02240706 Nct02632721mentioning

confidence: 99%

Unleashing Natural Killer Cells in the Tumor Microenvironment–The Next Generation of Immunotherapy?

2020

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“…To assess possible changes in NK cell function after TransIT-TKO transfection, we performed cytotoxicity assays using K562 to measure direct killing [32], and Rituximab (RTX)-coated autologous B cells to measure ADCC [33]. Prior to each assay, target cells (K562 or RTXcoated B cells) were stained with cell trace violet (CTV) (Thermofisher).…”

Section: Degranulation and Cytotoxicity Assaysmentioning

confidence: 99%

Highly efficient serum-free manipulation of miRNA in human NK cells without loss of viability or phenotypic alterations is accomplished with TransIT-TKO

2020

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Natural killer (NK) cells are innate lymphocytes with functions that include target cell killing, inflammation and regulation. NK cells integrate incoming activating and inhibitory signals through an array of germline-encoded receptors to gauge the health of neighbouring cells. The reactive potential of NK cells is influenced by microRNA (miRNA), small non-coding sequences that interfere with mRNA expression. miRNAs are highly conserved between species, and a single miRNA can have hundreds to thousands of targets and influence entire cellular programs. Two miRNA species, miR-155-5p and miR-146a-5p are known to be important in controlling NK cell function, but research to best understand the impacts of miRNA species within NK cells has been bottlenecked by a lack of techniques for altering miRNA concentrations efficiently and without off-target effects. Here, we describe a nonviral and straightforward approach for increasing or decreasing expression of miRNA in primary human NK cells. We achieve >90% transfection efficiency without off-target impacts on NK cell viability, education, phenotype or function. This opens the opportunity to study and manipulate NK cell miRNA profiles and their impacts on NK cellular programs which may influence outcomes of cancer, inflammation and autoimmunity.

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“…By virtue of the high expression of CD16 (Fc-ɣ-Receptor IIIa), NK cells can also be targeted via the Fc-part of therapeutic antibodies, which induces ADCC [6,12]. NK cells thus play a role in the treatment with cell-depleting antibodies [13][14][15][16].…”

Section: Introductionmentioning

confidence: 99%

CD3-(CD56 or 16)+ natural killer cell distribution in blood from healthy adults and patients with ANCA-associated vasculitis

Merkt¹,

Salzer²,

Thiel³

et al. 2020

Preprint

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BackgroundCytotoxic Natural Killer (NK) cells are an important target of new drugs entering the clinics, including checkpoint inhibitors and cell-depleting therapeutic antibodies. Still, basic blood NK cell parameters are poorly defined in healthy adults and in chronic inflammatory diseases like ANCA-associated vasculitis (AAV) which may alter the distribution of lymphocytes. The aims of this study were 1) to establish reference values of NK cell counts and percentages in healthy adults; 2) to describe these parameters in AAV; and 3) to investigate whether NK cell counts and percentages may be used as activity biomarker in the care of AAV patients, as suggested by a preceding study.MethodsCD3-(CD56 or 16)+ NK cell counts and percentages were determined in 120 healthy adults. Lymphocyte subset data from two German vasculitis centers were retrospectively analyzed (in total 407 measurements, including 201/49/157 measurements from 64/16/39 patients with granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA), respectively).ResultsCD3-(CD56 or 16)+ NK cell counts and percentages in healthy adults were highly variable, not Gaussian distributed and independent of age and sex. NK cell percentages ranged from 1.9 to 37.9% of lymphocytes, and were significantly more dispersed in AAV (0.3 to 57.6%). We further found that NK cell counts and percentages were different between AAV entities. However, during active disease, NK cell counts were consistently low in each AAV entity compared to healthy donors. NK cells were especially low in inactive EGPA. In 18% of EGPA patients we observed percentages of 1% or below which may be interpreted as temporary NK cell deficiency. Findings on differences between active and inactive GPA were discrepant between vasculitis centers.ConclusionsNK cell counts and percentages in blood are highly variable. This variability is further enhanced in systemic inflammatory diseases, and includes patients with temporary NK cell deficiency, in particular in EGPA. NK cell counts and percentages can presently not be recommended as biomarker in clinical care of AAV patients.

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Rituximab induces phenotypical and functional changes of NK cells in a non-malignant experimental setting

Cited by 22 publications

References 33 publications

Unleashing Natural Killer Cells in the Tumor Microenvironment–The Next Generation of Immunotherapy?

Unleashing Natural Killer Cells in the Tumor Microenvironment–The Next Generation of Immunotherapy?

Highly efficient serum-free manipulation of miRNA in human NK cells without loss of viability or phenotypic alterations is accomplished with TransIT-TKO

CD3-(CD56 or 16)+ natural killer cell distribution in blood from healthy adults and patients with ANCA-associated vasculitis

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