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Special Issue "Natural Killer and NKT Cells"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 June 2019).

Special Issue Editor

Guest Editor
Prof. Dr. Ingo Schmidt-Wolf Website E-Mail
Department of Integrated Oncology – CIO Bonn, University of Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany
Interests: immunooncology; cytokine-induced killer cells

Special Issue Information

Dear Colleagues,

This Special Issue, “Natural Killer (NK) and Natural Killer T (NKT) Cells”, will cover a selection of recent research topics and current review articles in this field. Experimental papers, up-to-date review articles, and commentaries are all welcome.

Natural Killer (NK) as well as Natural Killer T (NKT) cells represent exceptional lymphocyte populations with major tumor-killing activity. NK cells possess activating as well as inhibitory receptors. Most NKT cells recognize the antigen-presenting molecule CD1d. NKT cells are classified into type 1 invariant, type 2 diverse, and NKT-like cells. NK as well as NKT cells have been shown to play an essential role in autoimmune diseases as well as in cancer. NKT cells are present in peripheral blood mononuclear cells or cord blood in low numbers but can be expanded in vitro. Most clinical trials with NKT cells have been performed with Cytokine-Induced Killer (CIK) cells. CIK cells are licensed, e.g., in Germany.

Due to their easy availability and potent antitumor activity, NK and NKT cells have emerged as promising immunotherapeutic approaches in oncology and may become very important in the prognosis of cancer.

Prof. Dr. Ingo Schmidt-Wolf
Guest Editor

Manuscript Submission Information

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Keywords

  • NK cells
  • NKT cells
  • cytokine-induced killer cells
  • transplantation
  • immunotherapy
  • cancer treatment

Published Papers (10 papers)

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Research

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Open AccessArticle
Invariant Natural Killer T-Cells and Total CD1d Restricted Cells Differentially Influence Lipid Metabolism and Atherosclerosis in Low Density Receptor Deficient Mice
Int. J. Mol. Sci. 2019, 20(18), 4566; https://doi.org/10.3390/ijms20184566 - 14 Sep 2019
Abstract
Natural killer T (NKT) cells are a distinct subset of lymphocytes that bridge the innate and adaptive immune response and can be divided into type I invariant NKT cells (iNKT) and type II NKT cells. The objective of this study is to examine [...] Read more.
Natural killer T (NKT) cells are a distinct subset of lymphocytes that bridge the innate and adaptive immune response and can be divided into type I invariant NKT cells (iNKT) and type II NKT cells. The objective of this study is to examine the effects of NKT cell on lipid metabolism and the initiation and progression of atherosclerosis in LDL receptor deficient (LDLR−/−) mice. Mice were fed an atherogenic diet for 4 or 8 weeks and plasma lipids, lipoproteins, and atherosclerosis were measured. The selective absence of iNKT cells in Jα18−/−LDLR−/− mice led to an increase in plasma cholesterol levels in female mice. Transgenic Vα14tg/LDLR−/− mice with elevated numbers of iNKT cells had increased late atherosclerosis of the innominate artery, though absence of either iNKT cells or all NKT cells and other CD1d expressing cells had varying effects on atherosclerotic lesion burden in the ascending aortic arch and aortic root. These studies not only highlight the potential modulatory role played by NKT cells in atherosclerosis and lipid metabolism, but also raise the possibility that divergent roles may be played by iNKT and CD1d restricted cells such as type II NKT cells or other CD1d expressing cells. Full article
(This article belongs to the Special Issue Natural Killer and NKT Cells)
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Open AccessArticle
Improving the Clinical Application of Natural Killer Cells by Modulating Signals Signal from Target Cells
Int. J. Mol. Sci. 2019, 20(14), 3472; https://doi.org/10.3390/ijms20143472 - 15 Jul 2019
Abstract
Relapsed acute myeloid leukemia (AML) is a significant post-transplant complication lacking standard treatment and associated with a poor prognosis. Cellular therapy, which is already widely used as a treatment for several hematological malignancies, could be a potential treatment alternative. Natural killer (NK) cells [...] Read more.
Relapsed acute myeloid leukemia (AML) is a significant post-transplant complication lacking standard treatment and associated with a poor prognosis. Cellular therapy, which is already widely used as a treatment for several hematological malignancies, could be a potential treatment alternative. Natural killer (NK) cells play an important role in relapse control but can be inhibited by the leukemia cells highly positive for HLA class I. In order to restore NK cell activity after their ex vivo activation, NK cells can be combined with conditioning target cells. In this study, we tested NK cell activity against KG1a (AML cell line) with and without two types of pretreatment—Ara-C treatment that induced NKG2D ligands (increased activating signal) and/or blocking of HLA–KIR (killer-immunoglobulin-like receptors) interaction (decreased inhibitory signal). Both treatments improved NK cell killing activity. Compared with target cell killing of NK cells alone (38%), co-culture with Ara-C treated KG1a target cells increased the killing to 80%. Anti-HLA blocking antibody treatment increased the proportion of dead KG1a cells to 53%. Interestingly, the use of the combination treatment improved the killing potential to led to the death of 85% of KG1a cells. The combination of Ara-C and ex vivo activation of NK cells has the potential to be a feasible approach to treat relapsed AML after hematopoietic stem cell transplantation. Full article
(This article belongs to the Special Issue Natural Killer and NKT Cells)
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Open AccessArticle
Phase I Clinical Trial Using Autologous Ex Vivo Expanded NK Cells and Cytotoxic T Lymphocytes for Cancer Treatment in Vietnam
Int. J. Mol. Sci. 2019, 20(13), 3166; https://doi.org/10.3390/ijms20133166 - 28 Jun 2019
Abstract
(1) Background: Immune cell therapy recently attracted enormous attention among scientists as a cancer treatment, but, so far, it has been poorly studied and applied in Vietnam. The aim of this study was to assess the safety of autologous immune cell therapy for [...] Read more.
(1) Background: Immune cell therapy recently attracted enormous attention among scientists as a cancer treatment, but, so far, it has been poorly studied and applied in Vietnam. The aim of this study was to assess the safety of autologous immune cell therapy for treating lung, liver, and colon cancers—three prevalent cancers in Vietnam. (2) Method: This was an open-label, single-group clinical trial that included 10 patients with confirmed diagnosis of colon, liver, or lung cancer, conducted between March 2016 and December 2017. (3) Results: After 20–21 days of culture, the average number of cytotoxic T lymphocytes (CTLs) increased 488.5-fold and the average cell viability was 96.3%. The average number of natural killer cells (NKs) increased 542.5-fold, with an average viability of 95%. Most patients exhibited improved quality of life, with the majority of patients presenting a score of 1 to 2 in the Eastern Cooperative Oncology Group (ECOG) performance status (ECOG/PS) scale, a decrease in symptoms on fatigue scales, and an increase in the mean survival time to 18.7 months at the end of the study. (4) Conclusion: This method of immune cell expansion met the requirements for clinical applications in cancer treatment and demonstrated the safety of this therapy for the cancer patients in Vietnam. Full article
(This article belongs to the Special Issue Natural Killer and NKT Cells)
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Open AccessArticle
Cytotoxicity of Human Hepatic Intrasinusoidal CD56bright Natural Killer Cells against Hepatocellular Carcinoma Cells
Int. J. Mol. Sci. 2019, 20(7), 1564; https://doi.org/10.3390/ijms20071564 - 28 Mar 2019
Abstract
Hepatic intrasinusoidal (HI) natural killer (NK) cells from liver perfusate have unique features that are similar to those of liver-resident NK cells. Previously, we have reported that HI CD56bright NK cells effectively degranulate against SNU398 hepatocellular carcinoma (HCC) cells. Thus, the aim [...] Read more.
Hepatic intrasinusoidal (HI) natural killer (NK) cells from liver perfusate have unique features that are similar to those of liver-resident NK cells. Previously, we have reported that HI CD56bright NK cells effectively degranulate against SNU398 hepatocellular carcinoma (HCC) cells. Thus, the aim of this study was to further investigate the phenotype and function of HI NK cells. We found that HI CD56bright NK cells degranulated much less to Huh7 cells. HI CD56bright NK cells expressed NKG2D, NKp46, TNF-related apoptosis-inducing ligand (TRAIL), and FAS ligand (FASL) at higher levels than CD56dim cells. SNU398 cells expressed more NKG2D ligands and FAS and less PD-L1 than Huh7 cells. Blockade of NKG2D, TRAIL, and FASL significantly reduced the cytotoxicity of HI NK cells against SNU398 cells, but blockade of PD-L1 did not lead to any significant change. However, HI NK cells produced IFN-γ well in response to Huh7 cells. In conclusion, the cytotoxicity of HI CD56bright NK cells was attributed to the expression of NKG2D, TRAIL, and FASL. The results suggest the possible use of HI NK cells for cancer immunotherapy and prescreening of HCC cells to help identify the most effective NK cell therapy recipients. Full article
(This article belongs to the Special Issue Natural Killer and NKT Cells)
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Open AccessArticle
Abnormal Expression of c-Myc Oncogene in NK Cells in Patients with Cancer
Int. J. Mol. Sci. 2019, 20(3), 756; https://doi.org/10.3390/ijms20030756 - 11 Feb 2019
Abstract
Natural killer (NK) cells have received a lot of attention in recent years for the roles they play in immunity and particularly in antitumor immune responses. Although defects in NK cell functions are recognized as important mechanisms for immune evasion of malignant cells, [...] Read more.
Natural killer (NK) cells have received a lot of attention in recent years for the roles they play in immunity and particularly in antitumor immune responses. Although defects in NK cell functions are recognized as important mechanisms for immune evasion of malignant cells, molecular pathways regulating NK cell dysfunction and exhaustion in cancer are largely unknown. Here we tested whether the c-myc proto-oncogene, known to promote cell proliferation, growth, differentiation, and apoptosis by regulating the expression of numerous target genes, may be involved in the mechanism of NK cell abnormalities in patients with lung and gastric cancer. Analysis of c-myc mRNA and protein expression in peripheral blood NK cells, mitogen-activated protein kinase (MAPK) activity, cell cycle, and cell longevity revealed a significantly decreased expression of c-myc mRNA and protein and mitotic arrest of NK cells in different phases of cell cycle. In addition, a significant decrease of NK cell death was also detected. These data allow the suggestion that defects of NK cell-mediated tumor surveillance may be associated with disturbed c-myc expression in NK cells in cancer patients. A better understanding of the mechanisms of NK cell dysfunction in cancer will help in the NK cell-mediated therapeutic eradication of primary and metastatic cancer cells and prolong patient survival. Full article
(This article belongs to the Special Issue Natural Killer and NKT Cells)
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Review

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Open AccessReview
NK Cell Hyporesponsiveness: More Is Not Always Better
Int. J. Mol. Sci. 2019, 20(18), 4514; https://doi.org/10.3390/ijms20184514 - 12 Sep 2019
Abstract
Natural Killer (NK) cells are a type of cytotoxic lymphocytes that play an important role in the innate immune system. They are of particular interest for their role in elimination of intracellular pathogens, viral infection and tumor cells. As such, numerous strategies are [...] Read more.
Natural Killer (NK) cells are a type of cytotoxic lymphocytes that play an important role in the innate immune system. They are of particular interest for their role in elimination of intracellular pathogens, viral infection and tumor cells. As such, numerous strategies are being investigated in order to potentiate their functions. One of these techniques aims at promoting the function of their activating receptors. However, different observations have revealed that providing activation signals could actually be counterproductive and lead to NK cells’ hyporesponsiveness. This phenomenon can occur during the NK cell education process, under pathological conditions, but also after treatment with different agents, including cytokines, that are promising tools to boost NK cell function. In this review, we aim to highlight the different circumstances where NK cells become hyporesponsive and the methods that could be used to restore their functionality. Full article
(This article belongs to the Special Issue Natural Killer and NKT Cells)
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Open AccessReview
Clinical Trials with Combination of Cytokine-Induced Killer Cells and Dendritic Cells for Cancer Therapy
Int. J. Mol. Sci. 2019, 20(17), 4307; https://doi.org/10.3390/ijms20174307 - 03 Sep 2019
Abstract
Adoptive cellular immunotherapy (ACI) is a promising treatment for a number of cancers. Cytokine-induced killer cells (CIKs) are considered to be major cytotoxic immunologic effector cells. Usually cancer cells are able to suppress antitumor responses by secreting immunosuppressive factors. CIKs have significant antitumor [...] Read more.
Adoptive cellular immunotherapy (ACI) is a promising treatment for a number of cancers. Cytokine-induced killer cells (CIKs) are considered to be major cytotoxic immunologic effector cells. Usually cancer cells are able to suppress antitumor responses by secreting immunosuppressive factors. CIKs have significant antitumor activity and are capable of eradicating tumors with few side effects. They are a very encouraging cell population used against hematological and solid tumors, with an inexpensive expansion protocol which could yield to superior clinical outcome in clinical trials employing adoptive cellular therapy combination. In the last decade, clinical protocols have been modified by enriching lymphocytes with CIK cells. They are a subpopulation of lymphocytes characterized by the expression of CD3+ and CD56+ wich are surface markers common to T lymphocytes and natural killer NK cells. CIK cells are mainly used in two diseases: in hematological patients who suffer relapse after allogeneic transplantation and in patients with hepatic carcinoma after surgical ablation to eliminate residual tumor cells. Dendritic cells DCs could play a pivotal role in enhancing the antitumor efficacy of CIKs. Full article
(This article belongs to the Special Issue Natural Killer and NKT Cells)
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Open AccessReview
Hepatic Tumor Microenvironments and Effects on NK Cell Phenotype and Function
Int. J. Mol. Sci. 2019, 20(17), 4131; https://doi.org/10.3390/ijms20174131 - 24 Aug 2019
Abstract
The liver is a complex organ with critical physiological functions including metabolism, glucose storage, and drug detoxification. Its unique immune profile with large numbers of cytotoxic CD8+ T cells and significant innate lymphoid population, including natural killer cells, γ δ T cells, [...] Read more.
The liver is a complex organ with critical physiological functions including metabolism, glucose storage, and drug detoxification. Its unique immune profile with large numbers of cytotoxic CD8+ T cells and significant innate lymphoid population, including natural killer cells, γ δ T cells, MAIT cells, and iNKTcells, suggests an important anti-tumor surveillance role. Despite significant immune surveillance in the liver, in particular large NK cell populations, hepatic cell carcinoma (HCC) is a relatively common outcome of chronic liver infection or inflammation. The liver is also the second most common site of metastatic disease. This discordance suggests immune suppression by the environments of primary and secondary liver cancers. Classic tumor microenvironments (TME) are poorly perfused, leading to accumulation of tumor cell metabolites, diminished O2, and decreased nutrient levels, all of which impact immune cell phenotype and function. Here, we focus on changes in the liver microenvironment associated with tumor presence and how they affect NK function and phenotype. Full article
(This article belongs to the Special Issue Natural Killer and NKT Cells)
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Open AccessReview
Roles of Natural Killer T Cells and Natural Killer Cells in Kidney Injury
Int. J. Mol. Sci. 2019, 20(10), 2487; https://doi.org/10.3390/ijms20102487 - 20 May 2019
Abstract
Mouse natural killer T (NKT) cells and natural killer (NK) cells are innate immune cells that are highly abundant in the liver. In addition to their already-known antitumor and antimicrobial functions, their pathophysiological roles in the kidney have recently become evident. Under normal [...] Read more.
Mouse natural killer T (NKT) cells and natural killer (NK) cells are innate immune cells that are highly abundant in the liver. In addition to their already-known antitumor and antimicrobial functions, their pathophysiological roles in the kidney have recently become evident. Under normal circumstances, the proportion of activated NKT cells in the kidney increases with age. Administration of a synthetic sphingoglycolipid ligand (alpha-galactosylceramide) further activates NKT cells, resulting in injury to renal vascular endothelial cells via the perforin-mediated pathway and tubular epithelial cells via the TNF-α/Fas ligand pathway, causing acute kidney injury (AKI) with hematuria. Activation of NKT cells by common bacterial DNA (CpG-ODN) also causes AKI. In addition, NKT cells together with B cells play significant roles in experimental lupus nephritis in NZB/NZW F1 mice through their Th2 immune responses. Mouse NK cells are also assumed to be involved in various renal diseases, and there may be complementary roles shared between NKT and NK cells. Human CD56+ T cells, a functional counterpart of mouse NKT cells, also damage renal cells through a mechanism similar to that of mice. A subpopulation of human CD56+ NK cells also exert strong cytotoxicity against renal cells and contribute to the progression of renal fibrosis. Full article
(This article belongs to the Special Issue Natural Killer and NKT Cells)
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Open AccessReview
Natural Killer Immunotherapy for Minimal Residual Disease Eradication Following Allogeneic Hematopoietic Stem Cell Transplantation in Acute Myeloid Leukemia
Int. J. Mol. Sci. 2019, 20(9), 2057; https://doi.org/10.3390/ijms20092057 - 26 Apr 2019
Abstract
The most common cause of death in patients with acute myeloid leukemia (AML) who receive allogeneic hematopoietic stem cell transplantation (allo-HSCT) is AML relapse. Therefore, additive therapies post allo-HSCT have significant potential to prevent relapse. Natural killer (NK)-cell-based immunotherapies can be incorporated into [...] Read more.
The most common cause of death in patients with acute myeloid leukemia (AML) who receive allogeneic hematopoietic stem cell transplantation (allo-HSCT) is AML relapse. Therefore, additive therapies post allo-HSCT have significant potential to prevent relapse. Natural killer (NK)-cell-based immunotherapies can be incorporated into the therapeutic armamentarium for the eradication of AML cells post allo-HSCT. In recent studies, NK cell-based immunotherapies, the use of adoptive NK cells, NK cells in combination with cytokines, immune checkpoint inhibitors, bispecific and trispecific killer cell engagers, and chimeric antigen receptor-engineered NK cells have all shown antitumor activity in AML patients. In this review, we will discuss the current strategies with these NK cell-based immunotherapies as possible therapies to cure AML patients post allo-HSCT. Additionally, we will discuss various means of immune escape in order to further understand the mechanism of NK cell-based immunotherapies against AML. Full article
(This article belongs to the Special Issue Natural Killer and NKT Cells)
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