ORCID Profile
0000-0002-7921-1171
Current Organisation
Univesity of Toyama
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Publisher: Wiley
Date: 29-05-2015
DOI: 10.1111/CAS.12685
Publisher: Oxford University Press (OUP)
Date: 28-06-2011
DOI: 10.1189/JLB.0411208
Abstract: NK cells are effector lymphocytes playing a critical role in the natural resistance against tumors. However, the precise mechanisms underlying NK cell-mediated natural resistance against tumor metastasis are still unrevealed. B16 cells, mouse melanoma cells, were resistant to freshly isolated NK cell-mediated killing nevertheless, NK cells were critical for natural resistance against experimental lung metastasis of B16 cells. We found that lung metastasis was increased significantly in IFN-γ–/– mice but not pfp–/–, IFN-αR–/–, or IL-12/IL-18–/– mice. Interestingly, freshly isolated lung NK cells, but not spleen or liver NK cells, displayed augmented IFN-γ production after B16 inoculation. Adoptive transfer of pfp–/– NK cells, but not IFN-γ–/– NK cells, significantly decreased B16 lung metastasis in IFN-γ–/– and pfp/IFN-γ–/–mice. Lung metastases of IFN-γRDN B16 was also increased in NK cell-depleted or IFN-γ–/– mice, suggesting that the IFN-γ response of host cells was required in the NK cell and IFN-γ-mediated antimetastatic effect. Our results demonstrate that IFN-γ production from lung resident NK cells is a key response in the natural resistance to the experimental lung metastasis of NK cell-resistant tumor cells.
Publisher: Georg Thieme Verlag KG
Date: 02-09-2021
DOI: 10.1055/A-1585-5877
Publisher: Rockefeller University Press
Date: 09-02-2004
DOI: 10.1084/JEM.20031457
Abstract: Because tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) preferentially induces apoptosis in tumor cells and plays a critical role in tumor surveillance, its receptor is an attractive target for antibody-mediated tumor therapy. Here we report that a monoclonal antibody (mAb) against the mouse TRAIL receptor, DR5, exhibited potent antitumor effects against TRAIL-sensitive tumor cells in vivo by recruiting Fc receptor–expressing innate immune cells, with no apparent systemic toxicity. Administration of the agonistic anti-DR5 mAb also significantly inhibited experimental and spontaneous tumor metastases. Notably, the anti-DR5 mAb-mediated tumor rejection by innate immune cells efficiently evoked tumor-specific T cell immunity that could also eradicate TRAIL-resistant variants. These results suggested that the antibody-based therapy targeting DR5 is an efficient strategy not only to eliminate TRAIL-sensitive tumor cells, but also to induce tumor-specific T cell memory that affords a long-term protection from tumor recurrence.
Publisher: Rockefeller University Press
Date: 14-01-2002
DOI: 10.1084/JEM.20011171
Abstract: Natural killer (NK) cells and interferon (IFN)-γ have been implicated in immune surveillance against tumor development. Here we show that tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) plays a critical role in the NK cell–mediated and IFN-γ–dependent tumor surveillance. Administration of neutralizing monoclonal antibody against TRAIL promoted tumor development in mice subcutaneously inoculated with a chemical carcinogen methylcholanthrene (MCA). This protective effect of TRAIL was at least partly mediated by NK cells and totally dependent on IFN-γ. In the absence of TRAIL, NK cells, or IFN-γ, TRAIL-sensitive sarcomas preferentially emerged in MCA-inoculated mice. Moreover, development of spontaneous tumors in p53+/− mice was also promoted by neutralization of TRAIL. These results indicated a substantial role of TRAIL as an effector molecule that eliminates developing tumors.
Publisher: Wiley
Date: 12-1999
Publisher: American Association for Cancer Research (AACR)
Date: 04-2018
Publisher: Royal Society of Chemistry (RSC)
Date: 2018
DOI: 10.1039/C8RA02955E
Publisher: Wiley
Date: 11-04-2019
DOI: 10.1111/JDI.13047
Publisher: The American Association of Immunologists
Date: 08-2004
DOI: 10.4049/JIMMUNOL.173.3.2143
Abstract: The major limiting factor in the successful application of adjuvant therapy for metastatic disease is the lack of adjuvant specificity that leads to severe side effects. Reasoning that T cells of the immune system are highly specific, we generated tumor-specific T cells by genetic modification of mouse primary T cells with a chimeric receptor reactive with the human breast cancer-associated Ag erbB-2. These T cells killed breast cancer cells and secreted IFN-γ in an Ag-specific manner in vitro. We investigated their use against metastatic breast cancer in mice in an adjuvant setting, and compared their effectiveness with the commonly applied adjuvants doxorubicin, 5-fluorouracil, and herceptin. Mice were inoculated orthotopically with the human erbB-2-expressing spontaneously metastatic mouse breast cancer 4T1.2 in mammary tissue, and the primary tumor was surgically removed 8 days later. Significant metastatic disease was demonstrated in lung and liver at the time of surgery on day 8 with increased tumor burden at later time points. T cell adjuvant treatment of day 8 metastatic disease resulted in dramatic increases in survival of mice, and this survival was significantly greater than that afforded by either doxorubicin, 5-fluorouracil, or herceptin.
Publisher: Wiley
Date: 06-2004
Publisher: American Association for Cancer Research (AACR)
Date: 27-09-2022
DOI: 10.1158/1541-7786.MCR-22-0369
Abstract: Among factors involved in cancer cells escaping from immune responses, an intrinsic defect in the IFNγ response is considered to be one of the major players allowing cancer cells to evade the host immunity. In this study, we investigated how tumor cells escape from the IFNγ-dependent immune response through the immunoediting process by analyzing originally established immune-escape variants of melanoma cells. We found that the immune-escape melanoma variants gained resistance to the IFNγ-induced oxidative stress response and identified glutathione-S-transferase-4 (GSTA4) as a critical molecule in this process. Furthermore, the immune escape melanoma variants acquired a greater metastatic ability by a GSTA4-dependent mechanism. Considering the importance of GSTA4 in controlling IFNγ responsiveness and the metastatic potential of other melanoma cells, our results highlight a novel mechanism whereby cancer cells escape from host immunity and gain metastatic ability by acquiring resistance to oxidative stress responses through the upregulation of GSTA4.
Publisher: Wiley
Date: 20-10-2021
DOI: 10.1111/CAS.15150
Abstract: From a mouse triple‐negative breast cancer cell line, 4T1, we previously established 4T1.3 clone with a high capacity to metastasize to bone after its orthotopic injection into mammary fat pad of immunocompetent mice. Subsequent analysis demonstrated that the interaction between cancer cells and fibroblasts in a bone cavity was crucial for bone metastasis focus formation arising from orthotopic injection of 4T1.3 cells. Here, we demonstrated that a member of the adhesion G‐protein–coupled receptor (ADGR) family, G‐protein–coupled receptor 56 (GPR56)/adhesion G‐protein–coupled receptor G1 (ADGRG1), was expressed selectively in 4T1.3 grown in a bone cavity but not under in vitro conditions. Moreover, fibroblasts present in bone metastasis sites expressed type III collagen, a ligand for GPR56/ADGRG1. Consistently, GPR56/ADGRG1 proteins were detected in tumor cells in bone metastasis foci of human breast cancer patients. Deletion of GPR56/ADGRG1 from 4T1.3 cells reduced markedly intraosseous tumor formation upon their intraosseous injection. Conversely, intraosseous injection of GPR56/ADGRG1‐transduced 4T1, TS/A (mouse breast cancer cell line), or MDA‐MB‐231 (human breast cancer cell line) exhibited enhanced intraosseous tumor formation. Furthermore, we proved that the cleavage at the extracellular region was indispensable for GPR56/ADGRG1‐induced increase in breast cancer cell growth upon its intraosseous injection. Finally, inducible suppression of Gpr56/Adgrg1 gene expression in 4T1.3 cells attenuated bone metastasis formation with few effects on primary tumor formation in the spontaneous breast cancer bone metastasis model. Altogether, GPR56/ADGRG1 can be a novel target molecule to develop a strategy to prevent and/or treat breast cancer metastasis to bone.
Publisher: Spandidos Publications
Date: 10-2004
DOI: 10.3892/OR.12.4.837
Publisher: The American Association of Immunologists
Date: 15-11-2002
Publisher: Hindawi Limited
Date: 2015
DOI: 10.1155/2015/801291
Publisher: MDPI AG
Date: 28-12-2017
DOI: 10.3390/IJMS19010089
Publisher: Elsevier BV
Date: 04-2002
DOI: 10.1016/S0952-7915(02)00316-3
Abstract: NKT cells are key players in the regulation of antitumor immunity, particularly in experimental models of tumor immunotherapy, such as IL-12 or alpha-galactosylceramide administration. They may also operate in natural antitumor immunity. NKT cells are best known for their immunosuppressive functions however, NKT cells interact with a range of other cell types (particularly dendritic cells and NK cells) and the outcome of NKT-cell stimulation depends on these and on the cytokine/co-stimulatory milieu.
Publisher: The American Association of Immunologists
Date: 12-2010
Abstract: Although NK cells are well known for their cytotoxic functions, they also produce an array of immunoregulatory cytokines and chemokines. During an immune response, NK cells are exposed to complex combinations of cytokines that influence their differentiation and function. In this study, we have examined the phenotypic and functional consequences of exposing mouse NK cells to IL-4, IL-12, IL-15, IL-18, and IL-21 and found that although all factors induced signs of maturation, characterized by decreased proliferation and IFN-γ secretion, distinct combinations induced unique cytokine secretion profiles. In contrast, the immunosuppressive factors IL-10 and TGF-β had little direct effect on NK cell effector functions. Sustained IL-18 signals resulted in IL-13 and GM-CSF production, whereas IL-12 and IL-21 induced IL-10 and TNF-α. Surprisingly, with the exception of IL-21, all cytokines suppressed cytotoxic function of NK cells at the expense of endogenous cytokine production suggesting that “helper-type” NK cells were generated. The cytokine signals also profoundly altered the cell surface phenotype of the NK cells—a striking ex le being the downregulation of the activating receptor NKG2D by IL-4 that resulted in decreased NKG2D-dependent killing. IL-4 exposure also modulated NKG2D expression in vivo suggesting it is functionally important during immune responses. This study highlights the plasticity of NK cell differentiation and suggests that the relative abundance of cytokines at sites of inflammation will lead to erse outcomes in terms of NK cell phenotype and interaction with the immune system.
Publisher: Wiley
Date: 06-2001
DOI: 10.1002/1521-4141(200106)31:6<1720::AID-IMMU1720>3.0.CO;2-U
Publisher: Bentham Science Publishers Ltd.
Date: 2004
Abstract: alpha-Galactosylceramide (alpha-GalCer), is a glycolipid which has been identified as a ligand recognized by a special group of immune T cells, known as invariant NKT cells. alpha-GalCer can powerfully activate invariant NKT cells to produce immunoregulatory cytokines, including interferon-gamma and IL-4, and thereby exert a variety of subsequent effects on other cells in the immune system. Recent studies have revealed the mechanism of alpha-GalCer-induced iNKT cell-activation in immune responses to tumors and microbes, and in the suppression of autoimmune diseases. In this review, we discuss the potential immunomodulatory activity of alpha-GalCer and its possible future application for clinical studies in humans.
Publisher: Spandidos Publications
Date: 20-10-2020
Publisher: Wiley
Date: 29-01-2014
DOI: 10.1111/CAS.12336
Publisher: Spandidos Publications
Date: 03-06-2014
Publisher: Public Library of Science (PLoS)
Date: 02-06-2015
Publisher: Wiley
Date: 12-07-2018
DOI: 10.1111/CAS.13703
Publisher: Spandidos Publications
Date: 11-05-2016
DOI: 10.3892/OL.2016.4554
Publisher: Hindawi Limited
Date: 2013
DOI: 10.1155/2013/849754
Publisher: Wiley
Date: 02-1998
Publisher: Springer Science and Business Media LLC
Date: 24-02-2017
DOI: 10.1038/NCOMMS14607
Abstract: Genetic evolution that occurs during cancer progression enables tumour heterogeneity, thereby fostering tumour adaptation, therapeutic resistance and metastatic potential. Immune responses are known to select (immunoedit) tumour cells displaying immunoevasive properties. Here we address the role of IFN-γ in mediating the immunoediting process. We observe that, in several mouse tumour models such as HA-expressing 4T1 mammary carcinoma cells, OVA-expressing EG7 lymphoma cells and CMS5 MCA-induced fibrosarcoma cells naturally expressing mutated extracellular signal-regulated kinase (ERK) antigen, the action of antigen-specific cytotoxic T cell (CTL) in vivo results in the emergence of resistant cancer cell clones only in the presence of IFN-γ within the tumour microenvironment. Moreover, we show that exposure of tumours to IFN-γ-producing antigen-specific CTLs in vivo results in copy-number alterations (CNAs) associated with DNA damage response and modulation of DNA editing/repair gene expression. These results suggest that enhanced genetic instability might be one of the mechanisms by which CTLs and IFN-γ immunoedits tumours, altering their immune resistance as a result of genetic evolution.
Publisher: Springer Science and Business Media LLC
Date: 1998
Publisher: Elsevier BV
Date: 02-2005
DOI: 10.1016/J.MOLIMM.2004.07.034
Abstract: Natural killer (NK) cells are innate effector lymphocytes necessary for defence against stressed, microbe-infected, or malignant cells. NK cells kill target cells by either of two major mechanisms that require direct contact between NK cells and target cells. In the first pathway, cytoplasmic granule toxins, predominantly a membrane-disrupting protein known as perforin, and a family of structurally related serine proteases (granzymes) with various substrate specificities, are secreted by exocytosis and together induce apoptosis of the target cell. The granule-exocytosis pathway potently activates cell-death mechanisms that operate through the activation of apoptotic cysteine proteases (caspases), but can also cause cell death in the absence of activated caspases. The second pathway involves the engagement of death receptors (e.g. Fas/CD95) on target cells by their cognate ligands (e.g. FasL) on NK cells, resulting in classical caspase-dependent apoptosis. The comparative role of these pathways in the pathophysiology of many diseases is being dissected by analyses of gene-targeted mice that lack these molecules, and humans who have genetic mutations affecting these pathways. We are also now learning that the effector function of NK cells is controlled by interactions involving specific NK cell receptors and their cognate ligands, either on target cells, or other cells of the immune system. This review will discuss the functional importance of NK cell cytotoxicity and the receptor/ligand interactions that control these processes.
Publisher: Elsevier BV
Date: 08-2016
Publisher: Humana Press
Date: 09-11-2009
DOI: 10.1007/978-1-60761-362-6_3
Abstract: Identification of natural killer (NK) cell subsets has gained attention with the recent discovery that mature mouse NK cells comprise two distinct stages. Delineation of the stages is performed using the markers CD27 and CD11b on gated NK cells. The significance of this finding is underpinned by recent discoveries that mature human NK cells can also be discriminated by differential expression of CD27. This chapter will describe the methods required for the purification of lymphocytes from blood and other organs and the delineation of NK cell subsets by flow cytometry.
Publisher: Elsevier BV
Date: 08-2021
Publisher: Elsevier BV
Date: 08-2021
Publisher: Spandidos Publications
Date: 07-2013
DOI: 10.3892/OL.2013.1434
Publisher: The American Association of Immunologists
Date: 02-2006
Publisher: The American Association of Immunologists
Date: 15-04-2007
DOI: 10.4049/JIMMUNOL.178.8.4764
Abstract: NK cells are important for the clearance of tumors, parasites, and virus-infected cells. Thus, factors that control NK cell numbers and function are critical for the innate immune response. A subset of NK cells express the inhibitory killer cell lectin-like receptor G1 (KLRG1). In this study, we identify that KLRG1 expression is acquired during periods of NK cell ision such as development and homeostatic proliferation. KLRG1+ NK cells are mature in phenotype, and we show for the first time that these cells have a slower in vivo turnover rate, reduced proliferative response to IL-15, and poorer homeostatic expansion potential compared with mature NK cells lacking KLRG1. Transfer into lymphopenic recipients indicate that KLRG1− NK cells are precursors of KLRG1+ NK cells and KLRG1 expression accumulates following cell ision. Furthermore, KLRG1+ NK cells represent a significantly greater proportion of NK cells in mice with enhanced NK cell numbers such as Cd45−/− mice. These data indicate that NK cells acquire KLRG1 on their surface during development, and this expression correlates with functional distinctions from other peripheral NK cells in vivo.
Publisher: Rockefeller University Press
Date: 15-11-2004
DOI: 10.1084/JEM.20041522
Abstract: Single and combination cytokines offer promise in some patients with advanced cancer. Many spontaneous and experimental cancers naturally express ligands for the lectin-like type-2 transmembrane stimulatory NKG2D immunoreceptor however, the role this tumor recognition pathway plays in immunotherapy has not been explored to date. Here, we show that natural expression of NKG2D ligands on tumors provides an effective target for some cytokine-stimulated NK cells to recognize and suppress tumor metastases. In particular, interleukin (IL)-2 or IL-12 suppressed tumor metastases largely via NKG2D ligand recognition and perforin-mediated cytotoxicity. By contrast, IL-18 required tumor sensitivity to Fas ligand (FasL) and surprisingly did not depend on the NKG2D–NKG2D ligand pathway. A combination of IL-2 and IL-18 stimulated both perforin and FasL effector mechanisms with very potent effects. Cytokines that stimulated perforin-mediated cytotoxicity appeared relatively more effective against tumor metastases expressing NKG2D ligands. These findings indicate that a rational choice of cytokines can be made given the known sensitivity of tumor cells to perforin, FasL, and tumor necrosis factor–related apoptosis-inducing ligand and the NKG2D ligand status of tumor metastases.
Publisher: Spandidos Publications
Date: 30-01-2015
Publisher: The American Association of Immunologists
Date: 15-06-2007
DOI: 10.4049/JIMMUNOL.178.12.7540
Abstract: This study demonstrates that type I IFNs are an early and critical regulator of NK cell numbers, activation, and antitumor activity. Using both IFNAR1- and IFNAR2-deficient mice, as well as an IFNAR1-blocking Ab, we demonstrate that endogenous type I IFN is critical for controlling NK cell-mediated antitumor responses in many experimental tumor models, including protection from methylcholanthrene-induced sarcomas, resistance to the NK cell-sensitive RMA-S tumor and cytokine immunotherapy of lung metastases. Protection from RMA-S afforded by endogenous type I IFN is more potent than that of other effector molecules such as IFN-γ, IL-12, IL-18, and perforin. Furthermore, cytokine immunotherapy using IL-12, IL-18, or IL-21 was effective in the absence of endogenous type I IFN, however the antimetastatic activity of IL-2 was abrogated in IFNAR-deficient mice, primarily due to a defect in IL-2-induced cytotoxic activity. This study demonstrates that endogenous type I IFN is a central mediator of NK cell antitumor responses.
Publisher: Proceedings of the National Academy of Sciences
Date: 16-07-2003
Abstract: Recent studies have revealed significant efficacy of the marine sponge glycolipid, α-galactosylceramide (α-GalCer), in treatment of experimental metastatic cancers, infections, and autoimmune diseases. However, the capacity of α-GalCer to prevent tumor development had never, to our knowledge, been evaluated in mouse models of chemical- and oncogene-dependent carcinogenesis. In this study, we demonstrate that long-term administration of soluble α-GalCer, spanning the time of tumor initiation, inhibits primary tumor formation in three different models: methylcholanthrene-induced sarcomas, mammary carcinomas in Her-2/neu transgenic mice, and spontaneous sarcomas in p53 – / – mice. Weekly treatment of mice with α-GalCer maintained lymphoid tissue natural killer cell and T cell activation and elevated serum IFN-γ and IL-4 concentrations. Consistent with the antimetastatic activity of α-GalCer, prevention of methylcholanthrene-induced sarcoma was IFN-γand tumor necrosis factor-related apoptosis-inducing ligand dependent, but not perforin-dependent. Taken together, our results demonstrate that NK1.1 + αβTCR + cell-based immune therapy can inhibit primary tumorigenesis.
Publisher: Rockefeller University Press
Date: 07-11-2005
DOI: 10.1084/JEM.20050953
Abstract: We showed previously that NKT cell–deficient TCR Jα18−/− mice are more susceptible to methylcholanthrene (MCA)-induced sarcomas, and that normal tumor surveillance can be restored by adoptive transfer of WT liver-derived NKT cells. Liver-derived NKT cells were used in these studies because of their relative abundance in this organ, and it was assumed that they were representative of NKT cells from other sites. We compared NKT cells from liver, thymus, and spleen for their ability to mediate rejection of the sarcoma cell line (MCA-1) in vivo, and found that this was a specialized function of liver-derived NKT cells. Furthermore, when CD4+ and CD4− liver-derived NKT cells were administered separately, MCA-1 rejection was mediated primarily by the CD4− fraction. Very similar results were achieved using the B16F10 melanoma metastasis model, which requires NKT cell stimulation with α-galactosylceramide. The impaired ability of thymus-derived NKT cells was due, in part, to their production of IL-4, because tumor immunity was clearly enhanced after transfer of IL-4–deficient thymus-derived NKT cells. This is the first study to demonstrate the existence of functionally distinct NKT cell subsets in vivo and may shed light on the long-appreciated paradox that NKT cells function as immunosuppressive cells in some disease models, whereas they promote cell-mediated immunity in others.
Publisher: Springer Science and Business Media LLC
Date: 09-04-2021
DOI: 10.1186/S12906-021-03291-5
Abstract: Morus alba L. bark has been widely used in traditional medicine for treating several inflammatory diseases, such as hypertension, diabetes mellitus and coughing however, the molecular mechanisms underlying its anti-inflammatory effects are not well understood. We examined the effects of an extract of Morus alba L. bark (MabE) on Toll-like receptor (TLR) ligand-induced activation of RAW264.7 macrophages using a luciferase reporter assay and immunoassays. For the in vivo experiment, we used an imiquimod-induced ear edema model to examine the anti-inflammatory effects of MabE. MabE inhibited the TLR ligand-induced activation of NF-κB in RAW264.7 cells without affecting their viability. Consistent with the inhibition of NF-κB activation, MabE also inhibited the production of IL-6 and IL-1β from TLR ligand-treated RAW264.7 cells. In vivo MabE treatment inhibited the ear swelling of IMQ-treated mice, in addition to the mRNA expression of IL-17A, IL-1β and COX-2. The increases in splenic γδT cells in IMQ-treated mice and the production of IL-17A from splenocytes were significantly inhibited by MabE treatment. Our study suggests that the anti-inflammatory effects of MabE on the activation of the macrophage cell line RAW246.7 by TLRs and IMQ-induced ear edema are through the inhibition of NF-κB activation and IL-17A-producing γδT cells, respectively.
Publisher: Springer Science and Business Media LLC
Date: 07-2022
Publisher: Impact Journals, LLC
Date: 17-04-2018
Publisher: The American Association of Immunologists
Date: 15-08-2005
Publisher: American Society of Hematology
Date: 15-03-2005
Publisher: Spandidos Publications
Date: 14-12-2018
DOI: 10.3892/OL.2017.7621
Publisher: The Japanese Society of Strategies for Cancer Research and Therapy
Date: 2004
DOI: 10.4993/ACRT.12.9
Publisher: Wiley
Date: 28-07-2021
DOI: 10.1111/CAS.15050
Abstract: For successful immunotherapy for cancer, it is important to understand the immunological status of tumor antigen‐specific CD8 + T cells in the tumor microenvironment during tumor progression. In this study, we monitored the behavior of B16OVA‐Luc cells in mice immunized with a model tumor antigen ovalbumin (OVA). Using bioluminescence imaging, we identified the time series of OVA‐specific CD8 + T‐cell responses during tumor progression: initial progression, immune control, and the escape phase. As a result of analyzing the status of tumor antigen‐specific CD8 + cells in those 3 different phases, we found that the expression of NKG2D defines tumor‐reacting effector CD8 + T cells. NKG2D may control the fate and TOX expression of tumor‐reacting CD8 + T cells, considering that NKG2D blockade in OVA‐vaccinated mice delayed the growth of the B16OVA‐Luc2 tumor and increased the presence of tumor‐infiltrating OVA‐specific CD8 + T cells.
Publisher: Elsevier BV
Date: 02-2003
Publisher: Spandidos Publications
Date: 2017
DOI: 10.3892/OR.2017.5672
Publisher: Wiley
Date: 02-2016
DOI: 10.1111/CAS.12857
Publisher: Microbiology Society
Date: 07-2020
DOI: 10.1099/MIC.0.000929
Abstract: Bis-(3′–5′)-cyclic dimeric guanosine monophosphate (c-di-GMP) is a second messenger known to control a variety of bacterial processes. The model cyanobacterium, Synechocystis sp. PCC 6803, has a score of genes encoding putative enzymes for c-di-GMP synthesis and degradation. However, most of them have not been functionally characterized. Here, we chose four genes in Synechocystis ( dgcA–dgcD ), which encode proteins with a GGDEF, diguanylate cyclase (DGC) catalytic domain and multiple Per-ARNT-Sim (PAS) conserved regulatory motifs, for detailed analysis. Purified DgcA, DgcB and DgcC were able to catalyze synthesis of c-di-GMP from two GTPs in vitro . DgcA had the highest activity, compared with DgcB and DgcC. DgcD did not show detectable activity. DgcA activity was specific for GTP and stimulated by the alent cations, magnesium or manganese. Full activity of DgcA required the presence of the multiple PAS domains, probably because of their role in protein dimerization or stability. Synechocystis mutants carrying single deletions of dgcA–dgcD were not affected in their growth rate or biofilm production during salt stress, suggesting that there was functional redundancy in vivo . In contrast, overexpression of dgcA resulted in increased biofilm formation in the absence of salt stress. In this study, we characterize the enzymatic and physiological function of DgcA–DgcD, and propose that the PAS domains in DgcA function in maintaining the enzyme in its active form.
Publisher: The American Association of Immunologists
Date: 2004
Publisher: Springer Science and Business Media LLC
Date: 2001
DOI: 10.1038/83416
Abstract: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in various tumor cells in vitro, but its physiological role in tumor surveillance remains unknown. Here, we report that TRAIL is constitutively expressed on murine natural killer (NK) cells in the liver and plays a substantial role in suppressing tumor metastasis. Freshly isolated NK cells, but not natural killer T cells or ordinary T cells, from the liver expressed cell surface TRAIL, which was responsible for spontaneous cytotoxicity against TRAIL-sensitive tumor cells in vitro along with perforin and Fas ligand (FasL). Administration of neutralizing monoclonal antibody against TRAIL significantly increased experimental liver metastases of several TRAIL-sensitive tumor cell lines. Such an anti-metastatic effect of TRAIL was not observed in NK cell-depleted mice or interferon-gamma-deficient mice, the latter of which lacked TRAIL on liver NK cells. These findings provide the first evidence for the physiological function of TRAIL as a tumor suppressor.
Publisher: Wiley
Date: 21-08-2011
Publisher: Springer Science and Business Media LLC
Date: 11-2002
DOI: 10.1038/NRC928
Publisher: Pharmaceutical Society of Japan
Date: 05-2021
Publisher: Wiley
Date: 28-02-2013
DOI: 10.1111/CAS.12112
Publisher: Springer Science and Business Media LLC
Date: 02-05-2004
DOI: 10.1038/NI1069
Publisher: Begell House
Date: 2004
DOI: 10.1615/CRITREVIMMUNOL.V24.I4.20
Abstract: The common gamma chain family of cytokine receptors plays a plethora of roles during the early development, activation, and terminal differentiation of the lymphocyte lineages. The most recently identified member of this family, the IL-21R, is expressed to varying degrees on B, T lymphocytes, and natural killer (NK) cells, whereas IL-21, is reportedly only produced by activated CD4+ T cells. In keeping with this expression pattern the IL-21:IL-21R interaction is important for the latter stages and function of all three lymphoid lineages. IL-21 is a regulator of A-cell differentiation to plasma cells as well as immunoglobulin class switching. In contrast, within the T-cell lineage, IL-21 acts as a co-stimulator of proliferation, enhances memory response, and modulates homeostasis. Within the innate immune system IL-21 has a role in the terminal differentiation of NK cells, enhancing cytotoxic function while also decreasing cellular viability. These immune maturation and stimulating functions have resulted in IL-21 being tested in a variety of models of immunity. In these contexts, IL-21 has shown very promising efficacy in a number of antitumor immune responses mediated by NK and or T lymphocytes.
Publisher: Wiley
Date: 05-05-2020
DOI: 10.1111/CAS.14418
Publisher: Elsevier BV
Date: 04-2022
Publisher: Wiley
Date: 14-07-2020
DOI: 10.1111/CAS.14538
Publisher: Springer Science and Business Media LLC
Date: 31-01-2020
Publisher: Elsevier BV
Date: 2010
Publisher: Springer Science and Business Media LLC
Date: 14-05-2021
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1541-7786.22527782
Abstract: S1. Establishment of immune-escape variants of B16OVA cells S2. Immune-escape variants of B16OVA cells respond to IFN-gamma S3. Establishment of GSTA4 over-expressing B16OVA cells and GSTA4 knock-down IMM2 cells S4. Tumor-infiltrating T cell population in IMM2 shCTRL and IMM2 shGSTA4 tumors S5. Expression of GSTA4 in metastatic B16 melanoma variants
Publisher: Elsevier BV
Date: 2003
DOI: 10.1016/S1074-7613(02)00502-2
Abstract: The TNF-related apoptosis-inducing ligand (TRAIL) offers great promise as a cancer therapeutic. Initially, soluble recombinant versions of the TRAIL molecule have exhibited specific tumoricidal activity against a variety of tumors alone, or in combination with other cancer treatments, and much anticipation awaits the outcomes from early clinical trials. More recently, the natural role of TRAIL has been explored in tumor and allogeneic bone marrow transplantation models in the mouse. Strikingly, the TRAIL effector pathway appears a vital component of immunosurveillance of spontaneous or resident tumor cells by both T cells and NK cells, stimulating more hope that manipulating TRAIL activity is a natural path to improved cancer immunotherapy.
Publisher: MDPI AG
Date: 06-04-2023
Abstract: DPP8/9 inhibition induces either pyroptotic or apoptotic cell death in hematological malignancies. We previously reported that treatment with the DPP8/9 inhibitor 1G244 resulted in apoptotic cell death in myeloma, and our current study further evaluates the mechanism of action of 1G244 in different blood cancer cell lines. Specifically, 1G244 inhibited DPP9 to induce GSDMD-mediated-pyroptosis at low concentrations and inhibited DPP8 to cause caspase-3-mediated-apoptosis at high concentrations. HCK expression is necessary to induce susceptibility to pyroptosis but does not participate in the induction of apoptosis. To further characterize this DPP8-dependent broad-spectrum apoptosis induction effect, we evaluated the potential antineoplastic role for an analog of 1G244 with higher DPP8 selectivity, tominostat (also known as 12 m). In vitro studies demonstrated that the cytotoxic effect of 1G244 at high concentrations was enhanced in tominostat. Meanwhile, in vivo work showed tominostat exhibited antitumor activity that was more effective on a cell line sensitive to 1G244, and at higher doses, it was also effective on a cell line resistant to 1G244. Importantly, the weight loss morbidity associated with increasing doses of 1G244 was not observed with tominostat. These results suggest the possible development of novel drugs with antineoplastic activity against selected hematological malignancies by refining and increasing the DPP8 selectivity of tominostat.
Publisher: Wiley
Date: 10-07-2019
DOI: 10.1002/PTR.6422
Publisher: Springer Science and Business Media LLC
Date: 07-12-2022
Publisher: Rockefeller University Press
Date: 19-12-2005
DOI: 10.1084/JEM.20051381
Abstract: The importance of immunoregulatory T cells has become increasingly apparent. Both CD4+CD25+ T cells and CD1d-restricted NKT cells have been reported to down-regulate tumor immunity in mouse tumor models. However, the relative roles of both T cell populations have rarely been clearly distinguished in the same tumor models. In addition, CD1d-restricted NKT cells have been reported to play a critical role not only in the down-regulation of tumor immunity but also in the promotion of the immunity. However, the explanation for these apparently opposite roles in different tumor models remains unclear. We show that in four mouse tumor models in which CD1d-restricted NKT cells play a role in suppression of tumor immunity, depletion of CD4+CD25+ T cells did not induce enhancement of immunosurveillance. Surprisingly, among the two subpopulations of CD1d-restricted NKT cells, Vα14Jα18+ (type I) and Vα14Jα18− (type II) NKT cells, type I NKT cells were not necessary for the immune suppression. These unexpected results may now resolve the paradox in the role of CD1d-restricted NKT cells in the regulation of tumor immunity, in that type II NKT cells may be sufficient for negative regulation, whereas protection has been found to be mediated by α-galactosylceramide–responsive type I NKT cells.
Publisher: The American Association of Immunologists
Date: 2009
Publisher: Elsevier BV
Date: 04-2021
Publisher: MDPI AG
Date: 14-08-2023
Abstract: Chimeric-antigen-receptor (CAR) T-cell therapy for CD19-expressing B-cell malignancies is already widely adopted in clinical practice. On the other hand, the development of CAR-T-cell therapy for T-cell malignancies is in its nascent stage. One of the potential targets is CD26, to which we have developed and evaluated the efficacy and safety of the humanized monoclonal antibody YS110. We generated second (CD28) and third (CD28/4-1BB) generation CD26-targeted CAR-T-cells (CD26-2G/3G) using YS110 as the single-chain variable fragment. When co-cultured with CD26-overexpressing target cells, CD26-2G/3G strongly expressed the activation marker CD69 and secreted IFNgamma. In vitro studies targeting the T-cell leukemia cell line HSB2 showed that CD26-2G/3G exhibited significant anti-leukemia effects with the secretion of granzymeB, TNFα, and IL-8, with 3G being superior to 2G. CD26-2G/3G was also highly effective against T-cell lymphoma cells derived from patients. In an in vivo mouse model in which a T-cell lymphoma cell line, KARPAS299, was transplanted subcutaneously, CD26-3G inhibited tumor growth, whereas 2G had no effect. Furthermore, in a systemic dissemination model in which HSB2 was administered intravenously, CD26-3G inhibited tumor growth more potently than 2G, resulting in greater survival benefit. The third-generation CD26-targeted CAR-T-cell therapy may be a promising treatment modality for T-cell malignancies.
Publisher: American Association for Cancer Research (AACR)
Date: 15-12-2021
DOI: 10.1158/0008-5472.CAN-21-2078
Abstract: This study identifies a novel SOX10/IRF4 pathway that regulates noncanonical induction of IRF1 independent of the JAK–STAT pathway and can be targeted to improve the efficacy of anti-PD-1 therapy in melanoma.
Publisher: American Society of Hematology
Date: 03-2005
DOI: 10.1182/BLOOD-2004-08-3262
Abstract: Tumor necrosis factor (TNF)–related apoptosis-inducing ligand (TRAIL) is a key effector molecule expressed by natural killer (NK) cells and has been shown to prevent tumor initiation, growth, and metastasis. Here we demonstrate that TRAIL is the dominant cytotoxic effector molecule expressed by NK cells in fetal mice. On birth and with age, NK cells develop full functional capacity, including the ability to secrete interferon γ (IFN-γ) and interleukin 13 (IL-13) and mediate perforin- and Fas ligand-mediated cytotoxicity. However, interestingly, a phenotypically immature TRAIL+ NK cell subpopulation is retained in the liver of adult mice, and its retention is dependent on IFN-γ but not dependent on host IL-12, IL-18, or endogenous host pathogens. Adoptive transfer of either adult liver or neonatal TRAIL+ NK cells resulted in the appearance of TRAIL- NK cells with a mature phenotype, suggesting that these TRAIL+ NK cells were indeed a precursor. Although inducers of IFN-γ stimulated TRAIL expression on mature NK cells, our data indicated that constitutive TRAIL expression was a hallmark of immature cytotoxic NK cells. This study is the first to describe the concomitant maturation of NK cell effector function with surface phenotype in vivo and implies an important defense role for NK cell TRAIL in the developing immune system.
Publisher: Cold Spring Harbor Laboratory
Date: 17-09-2021
Publisher: Pharmaceutical Society of Japan
Date: 12-2020
Publisher: Wiley
Date: 31-07-2022
DOI: 10.1111/CAS.15478
Abstract: T‐cell receptor (TCR)‐like Abs that specifically recognize antigenic peptides presented on MHC molecules have been developed for next‐generation cancer immunotherapy. Recently, we reported a rapid and efficient method to generate TCR‐like Abs using a rabbit system. We humanized previously generated rabbit‐derived TCR‐like Abs reacting Epstein–Barr virus peptide (BRLF1p, TYPVLEEMF) in the context of HLA‐A24 molecules, produced chimeric antigen receptor (CAR)‐T cells, and evaluated their antitumor effects using in vitro and in vivo tumor models. Humanization of the rabbit‐derived TCR‐like Abs using the complementarity‐determining region grafting technology maintained their specificity and affinity. We prepared a second‐generation CAR using single‐chain variable fragment of the humanized TCR‐like Abs and then transduced them into human T cells. The CAR‐T cells specifically recognized BRLF1p/MHC molecules and lysed the target cells in an antigen‐specific manner in vitro. They also demonstrated antitumor activity in a mouse xenograft model. We report the generation of CAR‐T cells using humanized rabbit‐derived TCR‐like Abs. Together with our established and efficient generation procedure for TCR‐like Abs using rabbits, our platform for the clinical application of humanized rabbit‐derived TCR‐like Abs to CAR‐T cells will help improve next‐generation cancer immunotherapy.
Publisher: Wiley
Date: 07-11-2006
Publisher: Pharmaceutical Society of Japan
Date: 10-2022
Publisher: MDPI AG
Date: 18-08-2023
DOI: 10.3390/NU15163638
Abstract: (1) Background: Although the important role of dietary energy intake in regulating both cancer progression and host immunity has been widely recognized, it remains unclear whether dietary calorie restriction (CR) has any impact on anti-tumor immune responses. (2) Methods: Using an immunogenic B16 melanoma cell expressing ovalbumin (B16-OVA), we examined the effect of the CR diet on B16-OVA tumor growth and host immune responses. To further test whether the CR diet affects the efficacy of cancer immunotherapy, we examined the effect of CR against anti-PD-1 monoclonal antibody (anti-PD-1 Ab) treatment. (3) Results: The CR diet significantly slowed down the tumor growth of B16-OVA without affecting both CD4+ and CD8+ T cell infiltration into the tumor. Although in vivo depletion of CD8+ T cells facilitated B16-OVA tumor growth in the control diet group, there was no significant change in the tumor growth in the CR diet group with or without CD8+ T cell-depletion. Anti-PD-1 Ab treatment lost its efficacy to suppress tumor growth along with the activation and metabolic shift of CD8+ T cells under CR condition. (4) Conclusions: Our present results suggest that a physical condition restricted in energy intake in cancer patients may impair CD8+ T cell immune surveillance and the efficacy of immunotherapy.
Publisher: Spandidos Publications
Date: 23-11-2022
DOI: 10.3892/OR.2022.8452
Publisher: Wiley
Date: 10-07-2009
Publisher: Elsevier BV
Date: 06-2023
Publisher: Elsevier BV
Date: 12-2001
Abstract: Natural killer (NK) cells and interferon- (IFN) gamma have been implicated in immune surveillance against tumor development. Here we show tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which is a type II membrane protein belonging to the TNF family and plays a critical role in the NK cell-mediated and IFN-gamma-dependent suppression of subcutaneous growth of TRAIL-sensitive tumors. Administration of a neutralizing monoclonal antibody against TRAIL promoted outgrowth of subcutaneously inoculated TRAIL-sensitive tumors (L929, LB27.4, and Renca) but not TRAIL-resistant tumors (P815 and B16). Such a protective effect of TRAIL against TRAIL-sensitive tumors was abrogated in NK cell-depleted or IFN-gamma-deficient mice. These results suggested a substantial role of TRAIL as the effector molecule that eliminates subcutaneously developing TRAIL-sensitive tumors.
Publisher: American Association for Cancer Research (AACR)
Date: 28-02-2018
Publisher: Wiley
Date: 06-2004
Publisher: The American Association of Immunologists
Date: 15-05-2010
Abstract: The blockade of immune suppression against antitumor responses is a particularly attractive strategy when combined with agents that promote tumor-specific CTLs. In this study, we have attempted to further improve the CTL induction and potent antitumor efficacy of a combination mAb-based therapy (termed “trimAb therapy”) that comprises tumor cell death-inducing anti-death receptor 5 mAb and immune activating anti-CD40 and anti-CD137 mAbs. Among trimAb-treated tumors, the infiltration of CD4+ Foxp3+ cells was greater in progressing tumors compared with stable tumors. Blockade of CTLA-4 (CD152)-mediated signals by an antagonistic mAb substantially increased the tumor rejection rate of trimAb therapy, although the immune responses of draining lymph node cells were not augmented. Interestingly, by comparison, additional treatment with agonistic anti-glucocorticoid-induced TNF receptor mAb, antagonistic anti-programmed death-1 (CD279) mAb, or agonistic anti-OX40 (CD134) mAb significantly augmented immune responses of draining lymph node cells, but did not augment the therapeutic effect of trimAb. CD4 T cell depletion reduced the antitumor effect of anti–CTLA-4 mAb treatment alone, but did not reduce the tumor rejection rate of trimAb in conjunction with anti–CTLA-4 mAb. Thus, the blockade of the CTLA-4–mediated inhibitory signal in tumor infiltrating CTL may be the most effective strategy to augment the effect of immune therapies that generate tumor-specific CTL.
Publisher: Elsevier
Date: 2006
Publisher: Elsevier BV
Date: 11-2022
Publisher: The American Association of Immunologists
Date: 15-02-2000
Publisher: The American Association of Immunologists
Date: 15-10-2003
Publisher: Ferrata Storti Foundation (Haematologica)
Date: 08-2007
Abstract: In vitro studies suggest that thalidomide has an immunoregulatory role and alters the marrow microenvironment. We assessed laboratory and clinical parameters in patients with myeloma treated with thalidomide as potential prognostic markers and looked for changes with therapy. Seventy-five patients with relapsed/refractory myeloma received thalidomide in a phase II trial. Serial s les of platelet-poor plasma and bone marrow were tested for angiogenic cytokines including vascular endothelial growth factor (VEGF), marrow microvessel-density (MVD), mast cells and CD57+ cell expression. The effects of these parameters on response rate (RR), progression-free survival (PFS) and overall survival (OS) were analyzed. Elevated baseline VEGF predicted for a superior RR (p=0.018) and PFS. Elevated CD57+ cells also predicted superior PFS (p=0.012). MVD did not predict for RR, PFS or OS, but MVD and VEGF fell significantly in responders. Multivariate analysis identified that inferior OS was associated with age >65 years (p=0.017), raised lactate dehydrogenase (p=0.001), raised hepatocyte growth factor levels (p=0.012) and low pre-treatment CD57+ cells (p<0.001). Our findings support the suggestion that thalidomide has anti-angiogenic and immunomodulatory effects in myeloma. The preferred method for assessing angiogenesis is plasma VEGF levels and the assessment of CD57+ cells for patients with myeloma receiving novel immunomodulatory drugs should be further investigated.
Publisher: Springer Science and Business Media LLC
Date: 05-11-2020
Publisher: Science Alert
Date: 15-02-2022
Publisher: Elsevier BV
Date: 06-2006
DOI: 10.1016/J.SMIM.2006.03.005
Abstract: NKG2D is a type II transmembrane-anchored glycoprotein expressed as a disulfide-linked homodimer on the surface of all mouse and human natural killer cells (NK cells). Stimulation of NK cells through NKG2D triggers cell-mediated cytotoxicity and in some cases induces the production of cytokines. NKG2D binds to family of ligands with structural homology to MHC class I, however, unlike conventional MHC class I molecules, NKG2D ligands often display up-regulated surface expression on stressed cells and are frequently over expressed by tumors. Recent evidence clearly implicates that NKG2D recognition plays an important role in tumor immune surveillance and that NKG2D primarily acts to trigger perforin-mediated apoptosis. The data begin to place the NKG2D pathway into the context of other recognition-effector systems used by NK cells.
Publisher: Elsevier BV
Date: 09-2017
DOI: 10.1016/J.XPHS.2017.03.031
Abstract: Macrophage reprogramming toward a tumor-attacking phenotype is a promising treatment strategy, yet such strategies are scarce and it is not clear how to combine them with cytotoxic therapies that are often used to treat solid tumors. Here, we evaluate whether a micelle-encapsulated proteasome inhibitor, that is, the peptide aldehyde drug MG132, which is cytotoxic to cancer cells, can reprogram macrophages to attack the tumor. Through in vitro studies, we demonstrated that the proteasome inhibition reduces nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling-a known promoter of tumor-supporting macrophages and chemoresistance-in both cancer cells and macrophages. In in vivo studies, we showed that, although free MG132 did not affect the macrophage phenotype in tumors even at its maximum tolerated dose, the micellar formulation of MG132 safely achieved simultaneous cancer cell killing and macrophage reprogramming, thereby enhancing the antitumor efficacy in a syngeneic, orthotopic breast cancer model.
Publisher: EMBO
Date: 15-10-2014
Abstract: Natural killer ( NK ) cells are an innate lymphoid cell lineage characterized by their capacity to provide rapid effector functions, including cytokine production and cytotoxicity. Here, we identify the Ikaros family member, Aiolos, as a regulator of NK ‐cell maturation. Aiolos expression is initiated at the point of lineage commitment and maintained throughout NK ‐cell ontogeny. Analysis of cell surface markers representative of distinct stages of peripheral NK ‐cell maturation revealed that Aiolos was required for the maturation in the spleen of CD 11b high CD 27 − NK cells. The differentiation block was intrinsic to the NK ‐cell lineage and resembled that found in mice lacking either T‐bet or Blimp1 however, genetic analysis revealed that Aiolos acted independently of all other known regulators of NK ‐cell differentiation. NK cells lacking Aiolos were strongly hyper‐reactive to a variety of NK ‐cell‐mediated tumor models, yet impaired in controlling viral infection, suggesting a regulatory function for CD 27 − NK cells in balancing these two arms of the immune response. These data place Aiolos in the emerging gene regulatory network controlling NK ‐cell maturation and function.
Publisher: American Association for Cancer Research (AACR)
Date: 02-2020
Publisher: Oxford University Press (OUP)
Date: 07-03-2008
Abstract: It has long been recognized that human NK cells can be ided into two phenotypically and functionally distinct subsets, based on their levels of expression of CD56. We recently found that CD27 distinguishes subsets of mature mouse NK cells. Here we report that CD27 can be used as a marker to discriminate human NK cell subsets. The majority of peripheral blood human NK cells were CD27(lo)/CD56(dim) NK cells, whereas the minor CD27(hi) NK cell population correspondingly displayed a CD56(bright) phenotype. Distinctions between CD27(lo) and CD27(hi) NK cells in their receptor expression and typical NK cell functions such as cytotoxicity and cytokine production can be easily delineated. Therefore, we propose the dual use of CD27 and CD56 as maturation/subset markers for human NK cells. The identification of CD27 subsets in both mice and humans will allow more accurate projections of the role of NK cell subsets in murine models of human pathologies where NK cells are involved.
Publisher: Japanese Pharmacological Society
Date: 2009
DOI: 10.1254/FPJ.134.13
Publisher: Wiley
Date: 10-2004
DOI: 10.1111/J.1349-7006.2004.TB02181.X
Abstract: Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF family of cytokines, which can induce apoptotic cell death in a variety of tumor cells by engaging the death receptors DR4 and DR5, while sparing most normal cells. Preclinical studies in mice and non-human primates have shown the potential utility of recombinant soluble TRAIL and agonistic anti-DR5 or DR4 antibodies for cancer therapy. Moreover, we have recently revealed a vital role for endogenously expressed TRAIL in immunosurveillance of developing and metastatic tumors. In this review, we summarize recent knowledge about TRAIL and its receptors as promising targets for cancer therapy.
Publisher: American Association for Cancer Research (AACR)
Date: 12-10-2011
Publisher: The American Association of Immunologists
Date: 15-05-2001
Publisher: The American Association of Immunologists
Date: 15-02-2004
DOI: 10.4049/JIMMUNOL.172.4.2048
Abstract: IL-21 is a recently identified cytokine that stimulates mouse NK cell effector functions in vitro. In this study we demonstrate that IL-21 achieves its stimulatory effect by inducing the development of mature NK cells into a large granular lymphocyte phenotype with heightened effector function. IL-21 treatment results in increased cell size and granularity and a corresponding decrease in cell viability and proliferative potential. These cells up-regulate the expression of the inhibitory CD94-NKG2A receptor complex and the activation markers CD154 and killer cell, lectin-like-receptor G1. Surprisingly, IL-21 treatment also results in down-regulation of the pan-NK marker, NK1.1. Coinciding with these cellular changes IL-21 enhances cytolytic capacity across a spectrum of target sensitivities and induces IL-10 and IFN-γ production. In vivo treatment with IL-21 results in a very similar activation and phenotypic maturation of NK cells as well as a potent increase in NK cell-mediated anti-tumor immunity that is perforin dependent. These developmental changes suggested that IL-21 functions to induce the terminal differentiation of mouse NK cells, resulting in heightened NK cell-mediated cytotoxicity and immune surveillance.
Publisher: The American Association of Immunologists
Date: 15-10-2008
Publisher: Wiley
Date: 06-03-2021
DOI: 10.1111/CAS.14842
Abstract: Tumor metastasis is the leading cause of death worldwide and involves an extremely complex process composed of multiple steps. Our previous study demonstrated that apoptosis signal‐regulating kinase 1 (ASK1) deficiency in mice attenuates tumor metastasis in an experimental lung metastasis model. However, the steps of tumor metastasis regulated by ASK1 remain unclear. Here, we showed that ASK1 deficiency in mice promotes natural killer (NK) cell‐mediated intravascular tumor cell clearance in the initial hours of metastasis. In response to tumor inoculation, ASK1 deficiency upregulated immune response‐related genes, including interferon‐gamma (IFNγ). We also revealed that NK cells are required for these anti‐metastatic phenotypes. ASK1 deficiency augmented cytokine production chemoattractive to NK cells possibly through induction of the ligand for NKG2D, a key activating receptor of NK cells, leading to further recruitment of NK cells into the lung. These results indicate that ASK1 negatively regulates NK cell‐dependent anti‐tumor immunity and that ASK1‐targeted therapy can provide a new tool for cancer immunotherapy to overcome tumor metastasis.
Publisher: Rockefeller University Press
Date: 29-08-2005
DOI: 10.1084/JEM.20050994
Abstract: The activation NKG2D receptor has been shown to play an important role in the control of experimental tumor growth and metastases expressing ligands for NKG2D however, a function for this recognition pathway in host protection from de novo tumorigenesis has never been demonstrated. We show that neutralization of NKG2D enhances the sensitivity of wild-type (WT) C57BL/6 and BALB/c mice to methylcholanthrene (MCA)-induced fibrosarcoma. The importance of the NKG2D pathway was additionally illustrated in mice deficient for either IFN-γ or tumor necrosis factor–related apoptosis-inducing ligand, whereas mice depleted of natural killer cells, T cells, or deficient for perforin did not display any detectable NKG2D phenotype. Furthermore, IL-12 therapy preventing MCA-induced sarcoma formation was also largely dependent on the NKG2D pathway. Although NKG2D ligand expression was variable or absent on sarcomas emerging in WT mice, sarcomas derived from perforin-deficient mice were Rae-1+ and immunogenic when transferred into WT syngeneic mice. These findings suggest an important early role for the NKG2D in controlling and shaping tumor formation.
Publisher: Springer Science and Business Media LLC
Date: 28-07-2017
DOI: 10.1038/CDD.2017.114
Publisher: Wiley
Date: 15-05-2014
DOI: 10.1111/CAS.12425
Publisher: MDPI AG
Date: 16-06-2022
DOI: 10.3390/MOLECULES27123865
Abstract: The present study aimed to investigate the effect of acridone alkaloids on cancer cell lines and elucidate the underlying molecular mechanisms. The ten acridone alkaloids from Atalantia monophyla were screened for cytotoxicity against LNCaP cell lines by a WST-8 assay. Then, the most potential acridone, buxifoliadine E, was evaluated on four types of cancer cells, namely prostate cancer (LNCaP), neuroblastoma (SH SY5Y), hepatoblastoma (HepG2), and colorectal cancer (HT29). The results showed that buxifoliadine E was able to significantly inhibit the proliferation of all four types of cancer cells, having the most potent cytotoxicity against the HepG2 cell line. Western blotting analysis was performed to assess the expression of signaling proteins in the cancer cells. In HepG2 cells, buxifoliadine E induced changes in the levels of Bid as well as cleaved caspase-3 and Bax through MAPKs, including Erk and p38. Moreover, the binding interaction between buxifoliadine E and Erk was investigated by using the Autodock 4.2.6 and Discovery Studio programs. The result showed that buxifoliadine E bound at the ATP-binding site, located at the interface between the N- and C-terminal lobes of Erk2. The results of this study indicate that buxifoliadine E suppressed cancer cell proliferation by inhibiting the Erk pathway.
Publisher: Wiley
Date: 04-1999
DOI: 10.1002/(SICI)1521-4141(199904)29:04<1390::AID-IMMU1390>3.0.CO;2-C
Publisher: American Chemical Society (ACS)
Date: 13-10-2017
Publisher: Informa UK Limited
Date: 17-02-2017
Publisher: Elsevier BV
Date: 09-2023
Publisher: The American Association of Immunologists
Date: 15-05-2006
Publisher: Springer Science and Business Media LLC
Date: 23-03-2021
Publisher: Wiley
Date: 12-2021
DOI: 10.1002/TKM2.1270
Abstract: In this study, we examined the anti‐inflammatory effect of fermented brown rice and rice bran with Aspergillus oryzae (FBRA) on acute and chronic inflammation mouse models. As an acute inflammation model, we used a 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA)‐induced ear edema model. As a chronic inflammation model, we used an imiquimod (IMQ)‐induced psoriasis model and ragweed pollen‐induced allergic rhinitis model. We also investigated the effect of FBRA on the expression of inflammatory mediators in skin biopsies from the imiquimod‐induced psoriasis model. The mice fed the 10% FBRA‐containing diet showed lower‐level inflammation among the three different experimental models. In the IMQ‐induced psoriasis model, mRNA expressions of IL‐17A, IL‐1β and COX‐2 were significantly inhibited in the skin tissue of mice fed 10% FBRA diet. Our data suggest the potential benefit of FBRA as a functional food to prevent excessive inflammation.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1541-7786.22527782.V1
Abstract: S1. Establishment of immune-escape variants of B16OVA cells S2. Immune-escape variants of B16OVA cells respond to IFN-gamma S3. Establishment of GSTA4 over-expressing B16OVA cells and GSTA4 knock-down IMM2 cells S4. Tumor-infiltrating T cell population in IMM2 shCTRL and IMM2 shGSTA4 tumors S5. Expression of GSTA4 in metastatic B16 melanoma variants
Publisher: Spandidos Publications
Date: 19-02-2013
DOI: 10.3892/OR.2013.2293
Publisher: Informa UK Limited
Date: 11-05-2022
Publisher: The American Association of Immunologists
Date: 15-01-2004
Publisher: Springer Science and Business Media LLC
Date: 08-2006
DOI: 10.1038/NI0806-890
Publisher: The American Association of Immunologists
Date: 02-2006
Publisher: Pharmaceutical Society of Japan
Date: 1998
DOI: 10.1248/BPB.21.1154
Publisher: Portland Press Ltd.
Date: 14-02-2014
DOI: 10.1042/BJ20131463
Publisher: Informa UK Limited
Date: 25-04-2012
Publisher: Springer Science and Business Media LLC
Date: 27-04-2021
Publisher: Elsevier BV
Date: 09-2023
Publisher: Wiley
Date: 09-2016
DOI: 10.1111/CAS.13005
Publisher: Oxford University Press (OUP)
Date: 06-2000
Publisher: Proceedings of the National Academy of Sciences
Date: 02-05-2000
Publisher: Wiley
Date: 09-2016
DOI: 10.1111/CAS.13009
Publisher: Springer US
Date: 2007
Publisher: Oxford University Press (OUP)
Date: 16-10-2008
DOI: 10.1189/JLB.0707496
Abstract: The acquisition of inhibitory MHC-specific receptors occurs during NK cell differentiation and has been considered important in regulating NK cell responsiveness. NK cell differentiation has been studied on the basis of cell surface phenotype, function, and proliferative capacity. Together with phenotypically immature Mac-1lo NK cells, the mature Mac-1hi NK cell pool can be dissected further into two functionally distinct CD27hi and CD27lo subsets. Two major inhibitory receptors, CD94/NKG2A and Ly-49, are expressed on mouse NK cells. The acquisition of the CD94/NKG2A receptor seems to be an early event, whereas Ly-49 receptor expression is considered a relatively late event during NK cell ontogeny. In this study, we demonstrated a distinct NK cell inhibitory receptor repertoire formation within mature NK cell populations as defined by Mac-1 and CD27. By analyzing mice deficient in MHC class I expression or NKG2D ligand transgenic mice, we have shown that the inhibitory receptor repertoire can be modulated according to the differentiation/maturation status of NK cells, and the receptor acquisition is imprinted at an early stage of NK cell development by MHC class I interactions.
Publisher: Rockefeller University Press
Date: 08-03-2004
DOI: 10.1084/JEM.20031981
Abstract: Few studies have demonstrated that innate lymphocytes play a major role in preventing spontaneous tumor formation. We evaluated the development of spontaneous tumors in mice lacking β-2 microglobulin (β2m and thus MHC class I, CD1d, and CD16) and/or perforin, since these tumor cells would be expected to activate innate effector cells. Approximately half the cohort of perforin gene-targeted mice succumbed to spontaneous disseminated B cell lymphomas and in mice that also lacked β2m, the lymphomas developed earlier (by more than 100 d) and with greater incidence (84%). B cell lymphomas from perforin/β2m gene-targeted mice effectively primed cell-mediated cytotoxicity and perforin, but not IFN-γ, IL-12, or IL-18, was absolutely essential for tumor rejection. Activated NK1.1+ and γδTCR+ T cells were abundant at the tumor site, and transplanted tumors were strongly rejected by either, or both, of these cell types. Blockade of a number of different known costimulatory pathways failed to prevent tumor rejection. These results reflect a critical role for NK cells and γδTCR+ T cells in innate immune surveillance of B cell lymphomas, mediated by as yet undetermined pathway(s) of tumor recognition.
Publisher: Springer Science and Business Media LLC
Date: 09-07-2015
DOI: 10.1038/NCOMMS8679
Publisher: Elsevier BV
Date: 12-2018
DOI: 10.1016/J.BBRC.2018.11.068
Abstract: STAM-binding protein, STAMBP, is a JAMM-family deubiquitinating enzyme containing the microtubule-interacting/transport domain and STAM-binding domain. Although the biological importance of STAMBP in development has been recognized because the microcephaly-capillary malformation syndrome in human is caused by its somatic mutations, the role of STAMBP in cancer has not yet been determined. In this study, we demonstrate that STAMBP is a key molecule for regulating melanoma migration and invasion, but not survival, by knocking down STAMBP in vitro. STAMBP regulates SLUG expression through a post-transcriptional mechanism to control protein stability and further contributes to the in vivo metastatic potential of melanoma. Collectively, these results indicate the importance of STAMBP in melanoma metastasis by regulating SLUG. It is therefore a potential therapeutic target.
Publisher: Spandidos Publications
Date: 27-08-2014
Publisher: MDPI AG
Date: 24-02-2022
DOI: 10.3390/LIFE12030337
Abstract: The most common type of skin cancer is melanoma. While significant advances in chemotherapy have occurred in a few instances, only marginal progress has been made in treating metastatic melanoma. Natural medicine has traditionally been used to treat various illnesses, including cancer. The purpose of this study was to identify the active compound in Kaempferia galanga, which could be used to treat melanoma as an anti-metastasis and chemosensitizer agent. The active compound in K. galanga was isolated and identified using chromatography and spectroscopy techniques, and given six compounds. Inhibitory activity on NFκB activation and cell viability was determined using reporter assay methods. Among the isolated compounds, ethyl p-methoxycinnamate (EPMC) demonstrated potent NFκB inhibitory activity against melanoma cell B16F10- NFκB Luc2 with an IC50 of 88.7 μM. Further investigation was conducted by evaluating the anti-metastasis effect of EPMC in vitro by using wound-healing assays, invasion tests, and molecular mechanism assays using Western blotting. NFκB has been implicated in tumorigenesis through the PI3K/Akt/NFκB pathway. The results of this study indicated that EPMCs act as inhibitors of p38 and thereby Akt phosphorylation inhibitors at serine 473, inhibiting NFκB-dependent transcription. Further analysis with paclitaxel demonstrated that the combinations could sensitize to apoptosis in response to well-known chemotherapy agents. Additional studies were conducted using the human melanoma cancer cell line SK-Mel 28. Along with the induction of apoptosis, we observed an increase in p-γH2AX expression (a molecular marker for double strand breaks in DNA damage) in response to treatment with paclitaxel and EPMC. The result showed EPMC to be a potential, viable adjuvant for improving the clinical efficacy of anti-metastatic and cancer chemotherapy.
Publisher: Wiley
Date: 11-11-2004
DOI: 10.1111/J.0105-2896.2004.00199.X
Abstract: The concept that the immune system recognizes and controls cancer was first postulated over a century ago, and cancer immunity has continued to be vigorously debated and experimentally tested. Mounting evidence in humans and mice supports the involvement of cytokines in tumor initiation, growth, and metastasis. The idea that the immune system detects stressed, transformed, and frankly malignant cells underpins much of the excitement currently surrounding new cytokine therapies in cancer treatment. In this review, we define the contrasting roles that cytokines play in promoting tumor immunity, inflammation, and carcinogenesis. We also discuss the more promising aspects of clinical cytokine use in cancer patients.
Publisher: Elsevier BV
Date: 2020
Publisher: Wiley
Date: 13-05-2015
DOI: 10.1002/TKM2.1021
Publisher: Elsevier BV
Date: 11-2005
Publisher: Ivyspring International Publisher
Date: 2016
DOI: 10.7150/JCA.14713
Publisher: Spandidos Publications
Date: 16-10-2013
Publisher: Spandidos Publications
Date: 12-02-2015
DOI: 10.3892/OR.2015.3796
No related grants have been discovered for Yoshihiro Hayakawa.