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14 pages, 1843 KiB

Open AccessArticle

ABCC3 Expressed by CD56^dim CD16⁺ NK Cells Predicts Response in Glioblastoma Patients Treated with Combined Chemotherapy and Dendritic Cell Immunotherapy

by Serena Pellegatta, Natalia Di Ianni, Sara Pessina, Rosina Paterra, Elena Anghileri, Marica Eoli and Gaetano Finocchiaro

Int. J. Mol. Sci. 2019, 20(23), 5886; https://doi.org/10.3390/ijms20235886 - 23 Nov 2019

Cited by 17 | Viewed by 3716

Abstract

Recently, we found that temozolomide (TMZ) can upregulate the expression of the multidrug-resistance protein ABCC3 in NK cells from both glioma-bearing mice and glioblastoma patients treated with dendritic cell immunotherapy combined with TMZ, allowing NK cells to escape apoptosis and favoring their role [...] Read more.

Recently, we found that temozolomide (TMZ) can upregulate the expression of the multidrug-resistance protein ABCC3 in NK cells from both glioma-bearing mice and glioblastoma patients treated with dendritic cell immunotherapy combined with TMZ, allowing NK cells to escape apoptosis and favoring their role as antitumor effector cells. Here, we demonstrate that CD56^dim NK cells expressing CD16⁺ are predominant in patients surviving more than 12 months after surgery without disease progression. CD56^dim CD16⁺ NK cells co-expressed high levels of ABCC3 and IFN-γ. Notably, not only basal but also TMZ-induced ABCC3 expression was related to a strong, long-term NK cell response and a better prognosis of patients. The identification of the single nucleotide polymorphism (SNP) rs35467079 with the deletion of a cytosine (−897DelC) in the promoter region of the ABCC3 gene resulted associated with a better patient outcome. ABCC3 expression in patients carrying DelC compared to patients with reference haplotype was higher and modulated by TMZ. The transcription factor NRF2, involved in ABCC3 induction, was phosphorylated in CD56^dim CD16⁺ NK cells expressing ABCC3 under TMZ treatment. Thus, ABCC3 protein and the SNP −897DelC can play a predictive role in patients affected by GBM, and possibly other cancers, treated with dendritic cell immunotherapy combined with chemotherapy. Full article

(This article belongs to the Special Issue Natural Killer and NKT Cells)

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12 pages, 982 KiB

Open AccessArticle

Natural Killer Cell Function Tests by Flowcytometry-Based Cytotoxicity and IFN-γ Production for the Diagnosis of Adult Hemophagocytic Lymphohistiocytosis

by Hyeyoung Lee, Hoon Seok Kim, Jong-Mi Lee, Ki Hyun Park, Ae-Ran Choi, Jae-Ho Yoon, Hyejin Ryu and Eun-Jee Oh

Int. J. Mol. Sci. 2019, 20(21), 5413; https://doi.org/10.3390/ijms20215413 - 30 Oct 2019

Cited by 19 | Viewed by 4539

Abstract

Although natural killer (NK) cell function is a hallmark of hemophagocytic lymphohistiocytosis (HLH), there is no standard method or data on its diagnostic value in adults. Thus, we performed a single-center retrospective study of 119 adult patients with suspected HLH. NK cell function [...] Read more.

Although natural killer (NK) cell function is a hallmark of hemophagocytic lymphohistiocytosis (HLH), there is no standard method or data on its diagnostic value in adults. Thus, we performed a single-center retrospective study of 119 adult patients with suspected HLH. NK cell function was determined using both flowcytometry-based NK-cytotoxicity test (NK-cytotoxicity) and NK cell activity test for interferon-gamma (NKA-IFNγ). NK cell phenotype and serum cytokine levels were also tested. Fifty (42.0%) HLH patients showed significantly reduced NK cell function compared to 69 non-HLH patients by both NK-cytotoxicity and NKA-IFNγ (p < 0.001 and p = 0.020, respectively). Agreement between NK-cytotoxicity and NKA-IFNγ was 88.0% in HLH patients and 58.0% in non-HLH patients. NK-cytotoxicity and NKA-IFNγ assays predicted HLH with sensitivities of 96.0% and 92.0%, respectively. The combination of NKA-IFNγ and ferritin (>10,000 µg/L) was helpful for ruling out HLH, with a specificity of 94.2%. Decreased NK-cytotoxicity was associated with increased soluble IL-2 receptor levels and decreased CD56dim NK cells. Decreased NKA-IFNγ was associated with decreased serum cytokine levels. We suggest that both NK-cytotoxicity and NKA-IFNγ could be used for diagnosis of HLH. Further studies are needed to validate the diagnostic and prognostic value of NK cell function tests. Full article

(This article belongs to the Special Issue Natural Killer and NKT Cells)

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16 pages, 1491 KiB

Open AccessArticle

EGFR-Specific Tyrosine Kinase Inhibitor Modifies NK Cell-Mediated Antitumoral Activity against Ovarian Cancer Cells

by Nina Mallmann-Gottschalk, Yvonne Sax, Rainer Kimmig, Stephan Lang and Sven Brandau

Int. J. Mol. Sci. 2019, 20(19), 4693; https://doi.org/10.3390/ijms20194693 - 22 Sep 2019

Cited by 28 | Viewed by 4329

Abstract

The adverse prognosis of most patients with ovarian cancer is related to recurrent disease caused by resistance to chemotherapeutic and targeted therapeutics. Besides their direct activity against tumor cells, monoclonal antibodies and tyrosine kinase inhibitors (TKIs) also influence the antitumoral activity of immune [...] Read more.

The adverse prognosis of most patients with ovarian cancer is related to recurrent disease caused by resistance to chemotherapeutic and targeted therapeutics. Besides their direct activity against tumor cells, monoclonal antibodies and tyrosine kinase inhibitors (TKIs) also influence the antitumoral activity of immune cells, which has important implications for the design of immunotherapies. In this preclinical study, we treated different ovarian cancer cell lines with anti-epidermal growth factor receptor (EGFR) TKIs and co-incubated them with natural killer (NK) cells. We studied treatment-related structural and functional changes on tumor and immune cells in the presence of the anti-EGFR antibody cetuximab and investigated NK-mediated antitumoral activity. We show that long-term exposure of ovarian cancer cells to TKIs leads to reduced responsiveness of intrinsically sensitive cancer cells over time. Inversely, neither long-term treatment with TKIs nor cetuximab could overcome the intrinsic resistance of certain ovarian cancer cells to anti-EGFR agents. Remarkably, tumor cells pretreated with anti-EGFR TKIs showed increased sensitivity towards NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC). In contrast, the cytokine secretion of NK cells was reduced by TKI sensitization. Our data suggest that sensitization of tumor cells by anti-EGFR TKIs differentially modulates interactions with NK cells. These data have important implications for the design of chemo-immuno combination therapies in this tumor entity. Full article

(This article belongs to the Special Issue Natural Killer and NKT Cells)

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14 pages, 998 KiB

Open AccessArticle

Invariant Natural Killer T-Cells and Total CD1d Restricted Cells Differentially Influence Lipid Metabolism and Atherosclerosis in Low Density Receptor Deficient Mice

by Paul A. VanderLaan, Catherine A. Reardon, Veneracion G. Cabana, Chyung-Ru Wang and Godfrey S. Getz

Int. J. Mol. Sci. 2019, 20(18), 4566; https://doi.org/10.3390/ijms20184566 - 14 Sep 2019

Cited by 7 | Viewed by 3048

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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13 pages, 3071 KiB

Open AccessArticle

Improving the Clinical Application of Natural Killer Cells by Modulating Signals Signal from Target Cells

by Monika Holubova, Martin Leba, Hana Gmucova, Valentina S. Caputo, Pavel Jindra and Daniel Lysak

Int. J. Mol. Sci. 2019, 20(14), 3472; https://doi.org/10.3390/ijms20143472 - 15 Jul 2019

Cited by 4 | Viewed by 3146

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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15 pages, 398 KiB

Open AccessArticle

Phase I Clinical Trial Using Autologous Ex Vivo Expanded NK Cells and Cytotoxic T Lymphocytes for Cancer Treatment in Vietnam

by Nguyen Thanh Liem, Nguyen Van Phong, Nguyen Trung Kien, Bui Viet Anh, Truong Linh Huyen, Chu Thi Thao, Nguyen Dac Tu, Doan Trung Hiep, Do Thi Hoai Thu and Hoang Thi My Nhung

Int. J. Mol. Sci. 2019, 20(13), 3166; https://doi.org/10.3390/ijms20133166 - 28 Jun 2019

Cited by 19 | Viewed by 4757

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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15 pages, 2534 KiB

Open AccessArticle

Cytotoxicity of Human Hepatic Intrasinusoidal CD56^bright Natural Killer Cells against Hepatocellular Carcinoma Cells

by Shin Hwang, Jaeseok Han, Ji-Seok Baek, Eunyoung Tak, Gi-Won Song, Sung-Gyu Lee, Dong-Hwan Jung, Gil-Chun Park, Chul-Soo Ahn and Nayoung Kim

Int. J. Mol. Sci. 2019, 20(7), 1564; https://doi.org/10.3390/ijms20071564 - 28 Mar 2019

Cited by 17 | Viewed by 4803

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 CD56^bright 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 CD56^bright 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 CD56^bright NK cells degranulated much less to Huh7 cells. HI CD56^bright NK cells expressed NKG2D, NKp46, TNF-related apoptosis-inducing ligand (TRAIL), and FAS ligand (FASL) at higher levels than CD56^dim 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 CD56^bright 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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11 pages, 1071 KiB

Open AccessArticle

Abnormal Expression of c-Myc Oncogene in NK Cells in Patients with Cancer

by Gulnur K. Zakiryanova, Elena Kustova, Nataliya T. Urazalieva, Emile T. Baimuchametov, Narymzhan N. Nakisbekov and Michael R. Shurin

Int. J. Mol. Sci. 2019, 20(3), 756; https://doi.org/10.3390/ijms20030756 - 11 Feb 2019

Cited by 14 | Viewed by 4474

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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13 pages, 610 KiB

Open AccessReview

Invariant NKT Cells and Rheumatic Disease: Focus on Primary Sjogren Syndrome

by Chiara Rizzo, Lidia La Barbera, Marianna Lo Pizzo, Francesco Ciccia, Guido Sireci and Giuliana Guggino

Int. J. Mol. Sci. 2019, 20(21), 5435; https://doi.org/10.3390/ijms20215435 - 31 Oct 2019

Cited by 17 | Viewed by 3724

Abstract

Primary Sjogren syndrome (pSS) is a complex autoimmune disease mainly affecting salivary and lacrimal glands. Several factors contribute to pSS pathogenesis; in particular, innate immunity seems to play a key role in disease etiology. Invariant natural killer (NK) T cells (iNKT) are a [...] Read more.

Primary Sjogren syndrome (pSS) is a complex autoimmune disease mainly affecting salivary and lacrimal glands. Several factors contribute to pSS pathogenesis; in particular, innate immunity seems to play a key role in disease etiology. Invariant natural killer (NK) T cells (iNKT) are a T-cell subset able to recognize glycolipid antigens. Their function remains unclear, but studies have pointed out their ability to modulate the immune system through the promotion of specific cytokine milieu. In this review, we discussed the possible role of iNKT in pSS development, as well as their implications as future markers of disease activity. Full article

(This article belongs to the Special Issue Natural Killer and NKT Cells)

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20 pages, 1482 KiB

Open AccessReview

The Good and the Bad of Natural Killer Cells in Virus Control: Perspective for Anti-HBV Therapy

by Paola Fisicaro, Marzia Rossi, Andrea Vecchi, Greta Acerbi, Valeria Barili, Diletta Laccabue, Ilaria Montali, Alessandra Zecca, Amalia Penna, Gabriele Missale, Carlo Ferrari and Carolina Boni

Int. J. Mol. Sci. 2019, 20(20), 5080; https://doi.org/10.3390/ijms20205080 - 13 Oct 2019

Cited by 37 | Viewed by 7720

Abstract

Immune modulatory therapies are widely believed to represent potential therapeutic strategies for chronic hepatitis B infection (CHB). Among the cellular targets for immune interventions, Natural Killer (NK) cells represent possible candidates because they have a key role in anti-viral control by producing cytokines [...] Read more.

Immune modulatory therapies are widely believed to represent potential therapeutic strategies for chronic hepatitis B infection (CHB). Among the cellular targets for immune interventions, Natural Killer (NK) cells represent possible candidates because they have a key role in anti-viral control by producing cytokines and by exerting cytotoxic functions against virus-infected cells. However, in patients with chronic hepatitis B, NK cells have been described to be more pathogenic than protective with preserved cytolytic activity but with a poor capacity to produce anti-viral cytokines. In addition, NK cells can exert a regulatory activity and possibly suppress adaptive immune responses in the setting of persistent viral infections. Consequently, a potential drawback of NK-cell targeted modulatory interventions is that they can potentiate the suppressive NK cell effect on virus-specific T cells, which further causes impairment of exhausted anti-viral T cell functions. Thus, clinically useful NK-cell modulatory strategies should be not only suited to improve positive anti-viral NK cell functions but also to abrogate T cell suppression by NK cell-mediated T cell killing. This review outlines the main NK cell features with a particular focus on CHB infection. It describes different mechanisms involved in NK-T cell interplay as well as how NK cells can have positive anti-viral effector functions and negative suppressive effects on T cells activity. This review discusses how modulation of their balance can have potential therapeutic implications. Full article

(This article belongs to the Special Issue Natural Killer and NKT Cells)

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18 pages, 2278 KiB

Open AccessReview

SLAM-SAP-Fyn: Old Players with New Roles in iNKT Cell Development and Function

by Devika Bahal, Tanwir Hashem, Kim E. Nichols and Rupali Das

Int. J. Mol. Sci. 2019, 20(19), 4797; https://doi.org/10.3390/ijms20194797 - 27 Sep 2019

Cited by 3 | Viewed by 5505

Abstract

Invariant natural killer T (iNKT) cells are a unique T cell lineage that develop in the thymus and emerge with a memory-like phenotype. Accordingly, following antigenic stimulation, they can rapidly produce copious amounts of Th1 and Th2 cytokines and mediate activation of several [...] Read more.

Invariant natural killer T (iNKT) cells are a unique T cell lineage that develop in the thymus and emerge with a memory-like phenotype. Accordingly, following antigenic stimulation, they can rapidly produce copious amounts of Th1 and Th2 cytokines and mediate activation of several immune cells. Thus, it is not surprising that iNKT cells play diverse roles in a broad range of diseases. Given their pivotal roles in host immunity, it is crucial that we understand the mechanisms that govern iNKT cell development and effector functions. Over the last two decades, several studies have contributed to the current knowledge of iNKT cell biology and activity. Collectively, these studies reveal that the thymic development of iNKT cells, their lineage expansion, and functional properties are tightly regulated by a complex network of transcription factors and signaling molecules. While prior studies have clearly established the importance of the SLAM-SAP-Fyn signaling axis in iNKT cell ontogenesis, recent studies provide exciting mechanistic insights into the role of this signaling cascade in iNKT cell development, lineage fate decisions, and functions. Here we summarize the previous literature and discuss the more recent studies that guide our understanding of iNKT cell development and functional responses. Full article

(This article belongs to the Special Issue Natural Killer and NKT Cells)

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20 pages, 1124 KiB

Open AccessReview

NK Cell Hyporesponsiveness: More Is Not Always Better

by Marie Frutoso and Erwan Mortier

Int. J. Mol. Sci. 2019, 20(18), 4514; https://doi.org/10.3390/ijms20184514 - 12 Sep 2019

Cited by 16 | Viewed by 6512

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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21 pages, 865 KiB

Open AccessReview

Clinical Trials with Combination of Cytokine-Induced Killer Cells and Dendritic Cells for Cancer Therapy

by Francesca Garofano, Maria A. Gonzalez-Carmona, Dirk Skowasch, Roland Schmidt-Wolf, Alina Abramian, Stefan Hauser, Christian P. Strassburg and Ingo G. H. Schmidt-Wolf

Int. J. Mol. Sci. 2019, 20(17), 4307; https://doi.org/10.3390/ijms20174307 - 3 Sep 2019

Cited by 38 | Viewed by 6390

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

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17 pages, 3797 KiB

Open AccessReview

Hepatic Tumor Microenvironments and Effects on NK Cell Phenotype and Function

by Julián Piñeiro Fernández, Kimberly A. Luddy, Cathal Harmon and Cliona O’Farrelly

Int. J. Mol. Sci. 2019, 20(17), 4131; https://doi.org/10.3390/ijms20174131 - 24 Aug 2019

Cited by 77 | Viewed by 12821

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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13 pages, 798 KiB

Open AccessReview

Roles of Natural Killer T Cells and Natural Killer Cells in Kidney Injury

by Takahiro Uchida, Seigo Ito, Hiroo Kumagai, Takashi Oda, Hiroyuki Nakashima and Shuhji Seki

Int. J. Mol. Sci. 2019, 20(10), 2487; https://doi.org/10.3390/ijms20102487 - 20 May 2019

Cited by 21 | Viewed by 4956

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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17 pages, 1568 KiB

Open AccessReview

Natural Killer Immunotherapy for Minimal Residual Disease Eradication Following Allogeneic Hematopoietic Stem Cell Transplantation in Acute Myeloid Leukemia

by Norimichi Hattori and Tsuyoshi Nakamaki

Int. J. Mol. Sci. 2019, 20(9), 2057; https://doi.org/10.3390/ijms20092057 - 26 Apr 2019

Cited by 18 | Viewed by 6537

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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