Inhibition of Intracellular Antiviral Defense Mechanisms Augments Lentiviral Transduction of Human Natural Killer Cells: Implications for Gene Therapy

Sütlü, Tolga; Nyström, Sanna; Gilljam, Mari; Stellan, Birgitta; Applequist, Steven E.; Alici, Evren

doi:10.1089/hum.2012.080

Cited by 127 publications

(128 citation statements)

References 55 publications

Supporting

Mentioning

119

Contrasting

Unclassified

Order By: Relevance

“…For example, by using a cytokine combination (e.g., IL-2 + IL-15 or IL-2 + IL-21), the transduction efficiency into NK cells by VSV-G pseudotyped lentiviral vector was improved by approx. fivefold compared to single cytokine-stimulated NK cells [146]. In addition, inhibitors of intracellular antiviral responses were evaluated, and the results indicated that BX795 (an inhibitor of the TBK1/IKKe complex) improved the transduction efficiency by approx.…”

Section: Genetic Modification-gene Transfer To Nk Cellsmentioning

confidence: 99%

“…The lentiviral vectors RD114, 10A1, GALV, and VSV-G are used for the envelope of the viral vector, and RD114 and VSV-G seem to be suitable. However, it has been reported that viral vectors are recognized by antiviral mechanisms such as intracellular pattern recognition receptors, and apoptosis is induced [146]. The introduction efficiency was therefore not high.…”

Section: Genetic Modification-gene Transfer To Nk Cellsmentioning

confidence: 99%

See 1 more Smart Citation

Clinical Applications of Natural Killer Cells

Harada¹,

Teraishi²,

Ishii³

et al. 2017

Natural Killer Cells

View full text Add to dashboard Cite

Natural killer (NK) cells are an essential component of the innate immune system, and they play a crucial role in immunity against malignancies. Recent advances in our understanding of NK cell biology have paved the way for new therapeutic strategies based on NK cells for the treatment of various cancers. In this section, we will focus on NK cell immunotherapy, including the enhancement of antibody-dependent cellular cytotoxicity, the manipulation of receptor-mediated activation, inclusion criteria based on killer cell immunoglobulin-like receptor (KIR) ligand mismatches, and adoptive immunotherapy with ex vivo expanded chimeric antigen receptor (CAR)-engineered or engager-modified NK cells. In contrast to T lymphocytes, donor NK cells do not attack any recipient tissues based on allogeneic human leukocyte antigens (HLAs), suggesting that NK-mediated antitumor effects may be achieved without the risk of graft-versus-host disease (GvHD). Despite reports of clinical efficacy, the application of NK cell immunotherapy is limited. Developing strategies for manipulating NK cell products, host factors, and tumor targets are thus current subjects of diligent study. Research into the biology of NK cells has indicated that NK cell immunotherapy has the potential to become the forefront of cancer immunotherapy in the coming years.

show abstract

Section: Genetic Modification-gene Transfer To Nk Cellsmentioning

confidence: 99%

Section: Genetic Modification-gene Transfer To Nk Cellsmentioning

confidence: 99%

Clinical Applications of Natural Killer Cells

Harada¹,

Teraishi²,

Ishii³

et al. 2017

Natural Killer Cells

View full text Add to dashboard Cite

show abstract

“…The NK cells were cultured overnight in complete CellGro medium (CellGenix) supplemented with 500 U/ml IL-2 Proleukin S (Novartis) and expanded using the NK Cell Expansion Kit (Miltenyi Biotec). Transduction was repeated on 2 subsequent days using either a spinoculation protocol or a modified protocol according to Sutlu et al (52). Briefly, 1 3 10 5 NK cells per well were seeded in a 48-well plate (Corning) and mixed with 1.5 ml virus supernatant, 500 U/ml Proleukin S, 20 ng/ml human IL-21 (Miltenyi Biotec), and 8 mg/ml Polybrene (SigmaAldrich).…”

Section: Virus Production and Transduction Of Nk Cellsmentioning

confidence: 99%

DAP12-Based Activating Chimeric Antigen Receptor for NK Cell Tumor Immunotherapy

Töpfer

Cartellieri

Michen

et al. 2015

The Journal of Immunology

198

162

View full text Add to dashboard Cite

NK cells are emerging as new effectors for immunotherapy of cancer. In particular, the genetic engraftment of chimeric Ag receptors (CARs) in NK cells is a promising strategy to redirect NK cells to otherwise NK cell–resistant tumor cells. On the basis of DNAX-activation protein 12 (DAP12), a signaling adaptor molecule involved in signal transduction of activating NK cell receptors, we generated a new type of CAR targeting the prostate stem cell Ag (PSCA). We demonstrate in this article that this CAR, designated anti–PSCA-DAP12, consisting of DAP12 fused to the anti-PSCA single-chain Ab fragment scFv(AM1) confers improved cytotoxicity to the NK cell line YTS against PSCA-positive tumor cells when compared with a CAR containing the CD3ζ signaling chain. Further analyses revealed phosphorylation of the DAP12-associated ZAP-70 kinase and IFN-γ release of CAR-engineered cells after contact with PSCA-positive target cells. YTS cells modified with DAP12 alone or with a CAR bearing a phosphorylation-defective ITAM were not activated. Notably, infused YTS cells armed with anti–PSCA-DAP12 caused delayed tumor xenograft growth and resulted in complete tumor eradication in a significant fraction of treated mice. The feasibility of the DAP12-based CAR was further tested in human primary NK cells and confers specific cytotoxicity against KIR/HLA-matched PSCA-positive tumor cells, which was further enhanced by KIR-HLA mismatches. We conclude that NK cells engineered with DAP12-based CARs are a promising tool for adoptive tumor immunotherapy.

show abstract

“…EFTUD2 activates IRF3 to induce ISG expression through RLR signaling. To evaluate the role of RIG-I/MDA5 signaling in EFTUD2's antiviral effect, an RIG-I-like receptor (RLR) signaling inhibitor specifically targeting TBK1, BX795, was used to block RLR signaling in HCV-infected EFTUD2-overexpressing Huh7 and Huh7.5.1 cells (31). Compared with mock treatment, BX795 significantly increased HCV infection in JFH1-infected Huh7 cells with or without EFTUD2 overexpression (P Ͻ 0.01) (Fig.…”

Section: Eftud2 Induced Isg Expression Through Rig-i/mda5mentioning

confidence: 99%

EFTUD2 Is a Novel Innate Immune Regulator Restricting Hepatitis C Virus Infection through the RIG-I/MDA5 Pathway

Zhu

Xiao

Hong

et al. 2015

J Virol

View full text Add to dashboard Cite

The elongation factor Tu GTP binding domain-containing protein 2 (EFTUD2) was identified as an anti-hepatitis C virus (HCV) host factor in our recent genome-wide small interfering RNA (siRNA) screen. In this study, we sought to further determine EFTUD2's role in HCV infection and investigate the interaction between EFTUD2 and other regulators involved in HCV innate immune (RIG-I, MDA5, TBK1, and IRF3) and JAK-STAT1 pathways. We found that HCV infection decreased the expression of EFTUD2 and the viral RNA sensors RIG-I and MDA5 in HCV-infected Huh7 and Huh7.5.1 cells and in liver tissue from in HCVinfected patients, suggesting that HCV infection downregulated EFTUD2 expression to circumvent the innate immune response. H epatitis C virus (HCV) poses a threat to public health by infecting approximately 170 million people worldwide and causing chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (1, 2). Fifty to ninety percent of acute infections become chronic due to failure to mount a productive immune response to clear the virus. The innate immune system is the first line of defense responsible for recognizing viral pathogens and is therefore one of the crucial elements in determining the outcome of HCV infection.It is known that HCV RNA is recognized by the combined actions of protein kinase R (PKR), retinoic acid-inducible gene 1 (RIG-I), and Toll-like receptor 3 (TLR3) after viral entry into host cells (3-5). Pathogen recognition triggers downstream signaling to activate transcription factors, such as interferon (IFN) regulatory factors (IRFs), to induce type I interferon secretion and stimulation of the JAK-STAT signaling pathway, leading to the expression of IFN-stimulated genes (ISGs), which presumptively mediate control of viral replica-

show abstract

Inhibition of Intracellular Antiviral Defense Mechanisms Augments Lentiviral Transduction of Human Natural Killer Cells: Implications for Gene Therapy

Cited by 127 publications

References 55 publications

Clinical Applications of Natural Killer Cells

Clinical Applications of Natural Killer Cells

DAP12-Based Activating Chimeric Antigen Receptor for NK Cell Tumor Immunotherapy

EFTUD2 Is a Novel Innate Immune Regulator Restricting Hepatitis C Virus Infection through the RIG-I/MDA5 Pathway

Contact Info

Product

Resources

About