Inhibition of tumor metastasis by adoptive transfer of IL-12-activated V?14 NKT cells

Shin, Tahiro; Nakayama, Toshinori; Akutsu, Yasunori; Motohashi, Shinichiro; Shibata, Yoshiyuki; Harada, Michishige; Kamada, Noriaki; Shimizu, Chiaki; Shimizu, Eihan; Saito, Tsuyoshi; Ochiai, Takenori; Taniguchi, Masaru

doi:10.1002/1097-0215(20010215)91:4<523::aid-ijc1087>3.0.co;2-l

Cited by 59 publications

(37 citation statements)

References 41 publications

(46 reference statements)

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“…iNKT cells are a very small cell population in the peripheral blood before stimulation with aGalCer, a specific glycolipid antigen (Kawano et al, 1997;Brossay et al, 1998;Spada et al, 1998). After activation, the iNKT cell population significantly expands and exerts strong antitumor activity against various malignant tumors both in vivo and in vitro (Kawano et al, 1999;Shin et al, 2001;Seino et al, 2005). Therefore, we investigated the synergistic effects between vascular normalization with apelin and immunotherapy with aGalCer-pulsed DCs whose antitumor response had already reported in mice and humans (Nieda et al, 2004;Kunii et al, 2009;Motohashi et al, 2009).…”

Section: Apelin Induces Blood Vessel Enlargement In Tumors and Inhibimentioning

confidence: 99%

“…Invariant natural killer T (iNKT) cells are implicated in the control of autoimmunity (Singh et al, 2001), resistance to tumors (Shin et al, 2001;Smyth et al, 2002) and protection against infectious agents (Kakimi et al, 2000). The iNKT cells are characterized by the co-expression of natural killer (NK) receptor and T-cell receptor (TCR), which is encoded in humans by Va24-JaQ gene segments and in mice by homologous Va14-Ja281 sequences (Taniguchi et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

“…We previously reported that intravenous injection of aGalCer-pulsed dendritic cells (DCs) induced the activation of murine iNKT cells in vivo, and eradicated established metastatic tumor foci in models of mouse liver and lung metastasis (Shin et al, 2001). Based on these observations in murine models, several clinical trials of intravenous injection of aGalCer-pulsed DCs have been performed (Nieda et al, 2001;Motohashi et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

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The apelin/APJ system induces maturation of the tumor vasculature and improves the efficiency of immune therapy

et al. 2011

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Immature and unstable tumor vasculature provides an aberrant tumor microenvironment and leads to resistance of tumors to conventional therapy. Hence, normalization of tumor vessels has been reported to improve the effect of immuno-, chemo-and radiation therapy. However, the humoral factors, which can effectively induce maturation of tumor vasculature, have not been elucidated. In this study, we found that the novel peptide apelin and its receptor APJ can induce the morphological and functional maturation of blood vessels in tumors. This apelin-induced tumor vascular maturation enhances the efficacy of cancer dendritic cell-based immunotherapy and significantly suppresses tumor growth by promoting the infiltration of invariant natural killer T cells into the central region of the tumor and thereby robustly inducing apoptosis of tumor cells. Additionally, we showed APJ expression to be enhanced in the tumor endothelium in comparison with normal-state endothelial cells. These findings provide a new target for tumor vascular-specific maturation, which is expected to improve the efficacy of conventional cancer therapies.

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Section: Apelin Induces Blood Vessel Enlargement In Tumors and Inhibimentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The apelin/APJ system induces maturation of the tumor vasculature and improves the efficiency of immune therapy

et al. 2011

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“…8,23,33,50 Some experiments have suggested that NK cells are sufficient for IL-12-induced antitumor activity, 51 while a primary target of IL-12 antitumor activity was demonstrated to be V␣14 NKT cells. 23 Carnaud et al 52 suggested that with appropriate activation NKT cells can rapidly produce IFN-␥, which activates NK cells.…”

Section: Expansion Of Endogenous Lung V␣14 Nkt Cells After ␣-Galcer-pmentioning

confidence: 99%

Preserved IFN‐α production of circulating Vα24 NKT cells in primary lung cancer patients

Motohashi

Kobayashi

Ito

et al. 2002

Intl Journal of Cancer

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Human V␣24 NKT cells bearing an invariant V␣24J␣Q antigen receptor, the counterpart of murine V␣14 NKT cells, are activated by a specific ligand, ␣-GalCer, in a CD1d-dependent manner. Here, we demonstrate decreased numbers of circulating V␣24 NKT cells in patients with primary lung cancer compared to healthy volunteers. However, V␣24 NKT cells and DCs from lung cancer patients were functionally normal, even in the presence of tumor. Furthermore, levels of V␣24 NKT cells in surgically resected lung tissue appeared to be equivalent to those of V␣14 NKT cells in the mouse lung. Levels of V␣24 NKT cells in the tumor tissue itself were increased about 2.5 times. Administration of ␣-GalCer-pulsed DCs expanded V␣14 NKT cells in the lung more than 10 times, and the increased levels were sustained for 1 week. This may explain the previous finding that ␣-GalCer-pulsed DCs exerted strong antitumor activity in mouse lung tumor metastatic models. The potential use of ␣-GalCer-pulsed DCs for immunotherapy aimed at activating endogenous V␣24 NKT cells in the lung of cancer patients is discussed. © 2002 Wiley-Liss, Inc. Key words: V␣24 NKT cell; IFN-␥ primary lung cancer; ␣-galactosylceramide; single-cell sorting RT-PCRMurine V␣14 NKT cells are characterized by coexpression of NK1.1, an NK cell marker, and an invariant antigen receptor encoded by V␣14 and J␣281 gene segments. 1-3 V␣14 NKT cells recognize a glycolipid, ␣-GalCer, in a CD1d-depenent fashion. 4 The CD1d molecule has been well conserved throughout mammalian evolution and lacks allelic polymorphism. 5-7 After activation, V␣14 NKT cells inhibit tumor metastasis in certain experimental animal models. 8 -10 Furthermore, i.v. injection of ␣-GalCer-pulsed DCs expressed a potent antitumor effect in a B16 melanoma liver metastasis model, where metastasized tumor nodules were eradicated. 11 Human NKT cells bearing the invariant V␣24J␣Q receptor are considered to be the counterpart of murine V␣14 NKT cells and may recognize antigens similar to those of murine V␣14 NKT cells because of striking homology between human V␣24 and mouse V␣14 receptors, particularly in their complementarity-determining region 3. 2 Indeed, human V␣24 NKT cells were activated by ␣-GalCer in a CD1d-dependent fashion 5,12,13 and showed strong antitumor activity upon ␣-GalCer stimulation. 14,15 Human V␣24 NKT cells play crucial roles in various immune responses, including antitumor and autoimmune responses. 16 -19 These reports demonstrated selective reduction in V␣24 NKT cell numbers. Little is known, however, about the nature of V␣24 NKT cells in primary lung cancer patients.We investigated the function of V␣24 NKT cells in peripheral blood and lung of patients with lung cancer. The numbers of V␣24 NKT cells were reduced, whereas the function of freshly isolated V␣24 NKT cells appeared to be preserved in tumor-bearing patients. Furthermore, the ability to present ␣-GalCer by patient DCs was within a normal range. Administration of ␣-GalCer-pulsed DCs expanded V␣14 NKT cells in the lung more than 10 ti...

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“…Due to the ability of IL-12 to target, among other cells of the immune system, NK, NKT, and T cells, the antitumor activities of IL-12 have been demonstrated in both established and nonestablished tumor models. IL-12-induced antitumor activity in nonestablished tumor models is mediated mainly by NK and NKT cells, and conventional T cells are not required (3)(4)(5). Because both immunogenic (FBL-3, leukemia) and nonimmunogenic (Lewis lung carcinoma (LLC) and B16 melanoma) tumors were found to respond to IL-12 treatment equally in these nonestablished tumor models, tumor immunogenicity does not seem to play a significant role in the first type of IL-12-induced antitumor response.…”

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confidence: 99%

Pre-Existing Tumor-Sensitized T Cells Are Essential for Eradication of Established Tumors by IL-12 and Cyclophosphamide Plus IL-12

Lee

Tsung

et al. 2001

The Journal of Immunology

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The antitumor immune response activated by IL-12, especially by a combination of cyclophosphamide and IL-12 (Cy+IL-12), is clinically significant in certain experimental tumor models, in that a number of well-established (10–20 mm in diameter) s.c. tumors are completely eradicated. Furthermore, Cy+IL-12 treatment is also able to eradicate well-established grossly detectable experimental lung metastases and advanced ascites tumors. Despite the dramatic antitumor effects seen in some tumor models, Cy+IL-12 fails to induce regression of other established tumors. Characterization of tumor immunogenicity shows that all tumors responding to IL-12 and Cy+IL-12 treatments are immunogenic tumors, in that an antitumor immune response is detectable in tumor-bearing hosts upon tumor establishment. In contrast, none of the nonimmunogenic tumor responds to IL-12 and Cy+IL-12 treatments. Analysis of cellular requirements for successful tumor rejection through an adoptive cell transfer approach reveals that the presence of tumor-sensitized, but not naive, T cells is essential for tumor rejection by IL-12 and Cy+IL-12. Transfer of these tumor-sensitized T cells must be conducted before, but not after, IL-12 treatment in order for tumor rejection to occur. The requirement of sensitized T cells is also tumor specific. In mice bearing immunogenic tumors, the presence of pre-existing tumor-sensitized T cells is demonstrated by adoptive cell transfer experiments using purified spleen T cells from these mice. Results from our study show that Cy+IL-12-based immunotherapy of cancer may be highly effective and that pre-existing tumor-sensitized T cells are essential for the success of the therapy.

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Inhibition of tumor metastasis by adoptive transfer of IL-12-activated V?14 NKT cells

Cited by 59 publications

References 41 publications

The apelin/APJ system induces maturation of the tumor vasculature and improves the efficiency of immune therapy

The apelin/APJ system induces maturation of the tumor vasculature and improves the efficiency of immune therapy

Preserved IFN‐α production of circulating Vα24 NKT cells in primary lung cancer patients

Pre-Existing Tumor-Sensitized T Cells Are Essential for Eradication of Established Tumors by IL-12 and Cyclophosphamide Plus IL-12

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