Antitumor Activity of α-Galactosylceramide, KRN7000, in Mice With the Melanoma B16 Hepatic Metastasis and Immunohistological Study of Tumor Infiltrating Cells

Nakagawa, Ryusuke; Serizawa, Isao; Motoki, Kazuhiro; Sato, Miyuki; Ueno, Hikaru; Iijima, Rieko; Nakamura, Hiromi; Shimosaka, Akihiro; Koezuka, Yasuhiko

doi:10.3727/096504001108747521

Cited by 81 publications

(76 citation statements)

References 2 publications

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“…Several lines of evidence suggested that soluble factors produced by NKT cells activate NK cells to mediate the antitumor effects of ␣GalCer in vivo (12,22,23). Treatment of mice with ␣GalCer induced significant serum levels of IL-2, IL-4, IL-12, and IFN-␥ in a dose-dependent manner, and this correlated with augmented NK activity of hepatic mononuclear cells and marked growth inhibition of EL-4 lymphoma cells in liver (63).…”

Section: Figurementioning

confidence: 99%

Human NKT Cells Mediate Antitumor Cytotoxicity Directly by Recognizing Target Cell CD1d with Bound Ligand or Indirectly by Producing IL-2 to Activate NK Cells

Metelitsa

Naidenko

Kant

et al. 2001

The Journal of Immunology

319

273

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α-Galactosylceramide (αGalCer) stimulates NKT cells and has antitumor activity in mice. Murine NKT cells may directly kill tumor cells and induce NK cell cytotoxicity, but the mechanisms are not well defined. Newly developed human CD1d/αGalCer tetrameric complexes were used to obtain highly purified human αGalCer-reactive NKT cell lines (>99%), and the mechanisms of NKT cell cytotoxicity and activation of NK cells were investigated. Human NKT cells were cytotoxic against CD1d− neuroblastoma cells only when they were rendered CD1d+ by transfection and pulsed with αGalCer. Four other CD1d− tumor cell lines of diverse origin were resistant to NKT cells, whereas Jurkat and U937 leukemia cell lines, which are constitutively CD1d+, were killed. Killing of the latter was greatly augmented in the presence of αGalCer. Upon human CD1d/αGalCer recognition, NKT cells induced potent cytotoxicity of NK cells against CD1d− neuroblastoma cell lines that were not killed directly by NKT cells. NK cell activation depended upon NKT cell production of IL-2, and was enhanced by secretion of IFN-γ. These data demonstrate that cytotoxicity of human NKT cells can be CD1d and ligand dependent, and that TCR-stimulated NKT cells produce IL-2 that is required to induce NK cell cytotoxicity. Thus, NKT cells can mediate potent antitumor activity both directly by targeting CD1d and indirectly by activating NK cells.

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Section: Figurementioning

confidence: 99%

Human NKT Cells Mediate Antitumor Cytotoxicity Directly by Recognizing Target Cell CD1d with Bound Ligand or Indirectly by Producing IL-2 to Activate NK Cells

Metelitsa

Naidenko

Kant

et al. 2001

The Journal of Immunology

319

273

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“…10,11 Treatment of mice with the NKT cell ligand a-GalCer has been shown to have an antitumor effect in tumor metastasis models of the liver, lung and lymph nodes. [12][13][14][15] This effect is most likely caused by subsequent activation of NK cells, CTL and antigen presenting cells. 16 In 2 clinical phase 1 trials in advanced cancer patients injected with a-GalCer 17 or a-GalCer-loaded immature dendritic cells, 18 a distinct activation of the immune system was observed, but only in cancer patients with detectable Va24 þ Vb11 þ NKT cell numbers.…”

Section: Vb11mentioning

confidence: 99%

Peripheral blood IFN‐γ‐secreting Vα24⁺Vβ11⁺ NKT cell numbers are decreased in cancer patients independent of tumor type or tumor load

Molling

Kölgen

Vliet

et al. 2005

Intl Journal of Cancer

200

160

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Natural killer T (NKT) cells are CD1d-restricted lymphoid cells and are characterized by an invariant T-cell receptor, which in humans consists of a Va24 chain paired with a Vb11 chain. These cells are known for their rapid production of large amounts of cytokines (e.g., Vb11+ NKT cell numbers in both healthy controls and cancer patients and demonstrate that in both groups females have higher NKT cell levels compared to males. In a large group of 120 cancer patients, we show that circulating Va24+ NKT cell numbers are about 50% lower than in ageand gender-matched healthy controls and that this decrease is independent of tumor type or tumor load. This decrease was not restored upon tumor removal by means of surgery or radiotherapy. Even though the percentage of NKT cells that secrete IFN-g, as detected by ELISPOT, is normal in cancer patients, the absolute number of circulating IFN-g-secreting NKT cells is reduced. Together, our results suggest that the reduced circulating Va24 + Vb11+ NKT cell numbers in cancer patients are not affected by tumor load, but might actually reflect a risk factor for tumor development, e.g., by hampering efficient tumor immunosurveillance. ' 2005 Wiley-Liss, Inc.

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“…K RN7000, a marine sponge glycolipid with a novel ␣-galactosylceramide (␣-GalCer) structure, was found to exhibit potent antitumor activity in a variety of experimental and spontaneous tumor metastasis models (1)(2)(3)(4)(5)(6)(7). The antitumor effects of ␣-GalCer were first shown to be attributable to natural killer (NK) cell activation and the antigen presentation function of dendritic cells (8).…”

mentioning

confidence: 99%

α-Galactosylceramide (KRN7000) suppression of chemical- and oncogene-dependent carcinogenesis

Hayakawa

Rovero

Forni

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

145

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Recent studies have revealed significant efficacy of the marine sponge glycolipid, ␣-galactosylceramide (␣-GalCer), in treatment of experimental metastatic cancers, infections, and autoimmune diseases. However, the capacity of ␣-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 ␣-GalCer, spanning the time of tumor initiation, inhibits primary tumor formation in three different models: methylcholanthrene-induced sarcomas, mammary carcinomas in Her-2͞neu transgenic mice, and spontaneous sarcomas in p53 ؊/؊ mice. Weekly treatment of mice with ␣-GalCer maintained lymphoid tissue natural killer cell and T cell activation and elevated serum IFN-␥ and IL-4 concentrations. Consistent with the antimetastatic activity of ␣-GalCer, prevention of methylcholanthrene-induced sarcoma was IFN-␥-and tumor necrosis factor-related apoptosisinducing ligand dependent, but not perforin-dependent. Taken together, our results demonstrate that NK1.1 ؉ ␣␤TCR ؉ cell-based immune therapy can inhibit primary tumorigenesis. K RN7000, a marine sponge glycolipid with a novel ␣-galactosylceramide (␣-GalCer) structure, was found to exhibit potent antitumor activity in a variety of experimental and spontaneous tumor metastasis models (1-7). The antitumor effects of ␣-GalCer were first shown to be attributable to natural killer (NK) cell activation and the antigen presentation function of dendritic cells (8). ␣-GalCer was then identified as a ligand presented by CD1d to the invariant V␣14 T cell antigen receptor of mouse NK1.1 ϩ ␣␤TCR ϩ (NKT) cells (6, 9) and the invariant V␣24J␣QV␤11 TCR of human NKT cells (10). NKT cells have a range of characteristics that distinguish them from conventional T and NK cells (reviewed in refs. 11 and 12). In particular, upon stimulation, NKT cells have a remarkable capacity to produce immunoregulatory cytokines, including IL-4, IL-10, 13), that can powerfully influence the nature of adaptive immune responses. NKT cells also express a wide variety of cell death-inducing effector molecules and have been demonstrated to kill tumor target cells in vitro. Several studies have demonstrated the importance of NKT cells in immunoregulation, tumor immunity, and the prevention of autoimmune diseases in mice (reviewed in refs. 11 and 14-16).The antitumor activities of ␣-GalCer resemble those of IL-12, and a series of in vitro and in vivo studies (17)(18)(19)(20) have suggested that the initial steps that follow NKT cell TCR and CD1d͞␣-GalCer interaction involve IL-12 secretion by the antigenpresenting cell (21). In addition to these immediate events between NKT cells and dendritic cells, there are a series of consequences downstream, some of which result in the antitumor activity of ␣-GalCer (22-24). ␣-GalCer administration leads to rapid Th1 and Th2 cytokine production by NKT cells, and the activation of NKT cell IFN-␥ production rapidly results in NK cell act...

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Antitumor Activity of α-Galactosylceramide, KRN7000, in Mice With the Melanoma B16 Hepatic Metastasis and Immunohistological Study of Tumor Infiltrating Cells

Cited by 81 publications

References 2 publications

Human NKT Cells Mediate Antitumor Cytotoxicity Directly by Recognizing Target Cell CD1d with Bound Ligand or Indirectly by Producing IL-2 to Activate NK Cells

Human NKT Cells Mediate Antitumor Cytotoxicity Directly by Recognizing Target Cell CD1d with Bound Ligand or Indirectly by Producing IL-2 to Activate NK Cells

Peripheral blood IFN‐γ‐secreting Vα24⁺Vβ11⁺ NKT cell numbers are decreased in cancer patients independent of tumor type or tumor load

α-Galactosylceramide (KRN7000) suppression of chemical- and oncogene-dependent carcinogenesis

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Antitumor Activity of α-Galactosylceramide, KRN7000, in Mice With the Melanoma B16 Hepatic Metastasis and Immunohistological Study of Tumor Infiltrating Cells

Cited by 81 publications

References 2 publications

Human NKT Cells Mediate Antitumor Cytotoxicity Directly by Recognizing Target Cell CD1d with Bound Ligand or Indirectly by Producing IL-2 to Activate NK Cells

Human NKT Cells Mediate Antitumor Cytotoxicity Directly by Recognizing Target Cell CD1d with Bound Ligand or Indirectly by Producing IL-2 to Activate NK Cells

Peripheral blood IFN‐γ‐secreting Vα24+Vβ11+ NKT cell numbers are decreased in cancer patients independent of tumor type or tumor load

α-Galactosylceramide (KRN7000) suppression of chemical- and oncogene-dependent carcinogenesis

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Peripheral blood IFN‐γ‐secreting Vα24⁺Vβ11⁺ NKT cell numbers are decreased in cancer patients independent of tumor type or tumor load