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. 2001 Sep;85(5):741–746. doi: 10.1054/bjoc.2001.1973

In vitro anti-tumour activity of α-galactosylceramide-stimulated human invariant Vα24+NKT cells against melanoma

A Kikuchi 1,2, M Nieda 1, C Schmidt 2, Y Koezuka 3, S Ishihara 4, Y Ishikawa 1, K Tadokoro 1, S Durrant 5, A Boyd 2, T Juji 1, A Nicol 2,5
PMCID: PMC2364120  PMID: 11531261

Abstract

α-galactosylceramide (KRN 7000, α-GalCer) has shown potent in vivo anti-tumour activity in mice, including against melanoma and the highly specific effect of inducing proliferation and activation of human Vα24+NKT-cells. We hypothesized that human Vα24+NKT-cells activated by α-GalCer might exhibit anti-tumour activity against human melanoma. To investigate this, Vα24+NKT-cells were generated from the peripheral blood of patients with melanoma after stimulation with α-GalCer pulsed monocyte-derived dendritic cells (Mo-DCs). Vα24+NKT-cells did not exhibit cytolytic activity against the primary autologous or allogeneic melanoma cell lines tested. However, proliferation of the melanoma cell lines was markedly suppressed by co-culture with activated Vα24+NKT-cells (mean ± SD inhibition of proliferation 63.9 ± 1.3%). Culture supernatants of activated Vα24+NKT-cell cultures stimulated with α-GalCer pulsed Mo-DCs exhibited similar antiproliferative activities against melanoma cells, indicating that the majority of the inhibitory effects were due to soluble mediators rather than direct cell-to-cell interactions. This effect was predominantly due to release of IFN-γ, and to a lesser extent IL-12. Other cytokines, including IL-4 and IL-10, were released but these cytokines had less antiproliferative effects. These in vitro results show that Vα24+NKT-cells stimulated by α-GalCer-pulsed Mo-DCs have anti-tumour activities against human melanoma through antiproliferative effects exerted by soluble mediators rather than cytolytic effects as observed against some other tumours. Induction of local cytokine release by activated Vα24+NKT-cells may contribute to clinical anti-tumour effects of α-GalCer. © 2001 Cancer Research Campaign http://www.bjcancer.com

Keywords: melanoma, anti-tumour activity, Vα24+NKT-cells, α-GalCer, IFN-γ

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Selected References

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  1. Azzoni L., Zatsepina O., Abebe B., Bennett I. M., Kanakaraj P., Perussia B. Differential transcriptional regulation of CD161 and a novel gene, 197/15a, by IL-2, IL-15, and IL-12 in NK and T cells. J Immunol. 1998 Oct 1;161(7):3493–3500. [PubMed] [Google Scholar]
  2. Bezouska K., Yuen C. T., O'Brien J., Childs R. A., Chai W., Lawson A. M., Drbal K., Fiserová A., Pospísil M., Feizi T. Oligosaccharide ligands for NKR-P1 protein activate NK cells and cytotoxicity. Nature. 1994 Nov 10;372(6502):150–157. doi: 10.1038/372150a0. [DOI] [PubMed] [Google Scholar]
  3. Burdin N., Brossay L., Kronenberg M. Immunization with alpha-galactosylceramide polarizes CD1-reactive NK T cells towards Th2 cytokine synthesis. Eur J Immunol. 1999 Jun;29(6):2014–2025. doi: 10.1002/(SICI)1521-4141(199906)29:06<2014::AID-IMMU2014>3.0.CO;2-G. [DOI] [PubMed] [Google Scholar]
  4. Calabi F., Bradbury A. The CD1 system. Tissue Antigens. 1991 Jan;37(1):1–9. doi: 10.1111/j.1399-0039.1991.tb01836.x. [DOI] [PubMed] [Google Scholar]
  5. Couedel C., Peyrat M. A., Brossay L., Koezuka Y., Porcelli S. A., Davodeau F., Bonneville M. Diverse CD1d-restricted reactivity patterns of human T cells bearing "invariant" AV24BV11 TCR. Eur J Immunol. 1998 Dec;28(12):4391–4397. doi: 10.1002/(SICI)1521-4141(199812)28:12<4391::AID-IMMU4391>3.0.CO;2-2. [DOI] [PubMed] [Google Scholar]
  6. Cui J., Shin T., Kawano T., Sato H., Kondo E., Toura I., Kaneko Y., Koseki H., Kanno M., Taniguchi M. Requirement for Valpha14 NKT cells in IL-12-mediated rejection of tumors. Science. 1997 Nov 28;278(5343):1623–1626. doi: 10.1126/science.278.5343.1623. [DOI] [PubMed] [Google Scholar]
  7. Dellabona P., Padovan E., Casorati G., Brockhaus M., Lanzavecchia A. An invariant V alpha 24-J alpha Q/V beta 11 T cell receptor is expressed in all individuals by clonally expanded CD4-8- T cells. J Exp Med. 1994 Sep 1;180(3):1171–1176. doi: 10.1084/jem.180.3.1171. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Fujimoto T., O'Donnell M. A., Szilvasi A., Yang H., Duda R. B. Bacillus Calmette-Guérin plus interleukin-2 and/or granulocyte/macrophage-colony-stimulating factor enhances immunocompetent cell production of interferon-gamma, which inhibits B16F10 melanoma cell growth in vitro. Cancer Immunol Immunother. 1996 Jun;42(5):280–284. doi: 10.1007/s002620050283. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Gillis S., Williams D. E. Cytokine therapy: lessons learned and future challenges. Curr Opin Immunol. 1998 Oct;10(5):501–503. doi: 10.1016/s0952-7915(98)80213-6. [DOI] [PubMed] [Google Scholar]
  10. Kawano T., Cui J., Koezuka Y., Toura I., Kaneko Y., Motoki K., Ueno H., Nakagawa R., Sato H., Kondo E. CD1d-restricted and TCR-mediated activation of valpha14 NKT cells by glycosylceramides. Science. 1997 Nov 28;278(5343):1626–1629. doi: 10.1126/science.278.5343.1626. [DOI] [PubMed] [Google Scholar]
  11. Kawano T., Cui J., Koezuka Y., Toura I., Kaneko Y., Sato H., Kondo E., Harada M., Koseki H., Nakayama T. Natural killer-like nonspecific tumor cell lysis mediated by specific ligand-activated Valpha14 NKT cells. Proc Natl Acad Sci U S A. 1998 May 12;95(10):5690–5693. doi: 10.1073/pnas.95.10.5690. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Kawano T., Nakayama T., Kamada N., Kaneko Y., Harada M., Ogura N., Akutsu Y., Motohashi S., Iizasa T., Endo H. Antitumor cytotoxicity mediated by ligand-activated human V alpha24 NKT cells. Cancer Res. 1999 Oct 15;59(20):5102–5105. [PubMed] [Google Scholar]
  13. Kitamura H., Iwakabe K., Yahata T., Nishimura S., Ohta A., Ohmi Y., Sato M., Takeda K., Okumura K., Van Kaer L. The natural killer T (NKT) cell ligand alpha-galactosylceramide demonstrates its immunopotentiating effect by inducing interleukin (IL)-12 production by dendritic cells and IL-12 receptor expression on NKT cells. J Exp Med. 1999 Apr 5;189(7):1121–1128. doi: 10.1084/jem.189.7.1121. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Kobayashi E., Motoki K., Uchida T., Fukushima H., Koezuka Y. KRN7000, a novel immunomodulator, and its antitumor activities. Oncol Res. 1995;7(10-11):529–534. [PubMed] [Google Scholar]
  15. Nicol A., Nieda M., Koezuka Y., Porcelli S., Suzuki K., Tadokoro K., Durrant S., Juji T. Human invariant valpha24+ natural killer T cells activated by alpha-galactosylceramide (KRN7000) have cytotoxic anti-tumour activity through mechanisms distinct from T cells and natural killer cells. Immunology. 2000 Feb;99(2):229–234. doi: 10.1046/j.1365-2567.2000.00952.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Nieda M., Nicol A., Koezuka Y., Kikuchi A., Takahashi T., Nakamura H., Furukawa H., Yabe T., Ishikawa Y., Tadokoro K. Activation of human Valpha24NKT cells by alpha-glycosylceramide in a CD1d-restricted and Valpha24TCR-mediated manner. Hum Immunol. 1999 Jan;60(1):10–19. doi: 10.1016/s0198-8859(98)00100-1. [DOI] [PubMed] [Google Scholar]
  17. Takahashi T., Nieda M., Koezuka Y., Nicol A., Porcelli S. A., Ishikawa Y., Tadokoro K., Hirai H., Juji T. Analysis of human V alpha 24+ CD4+ NKT cells activated by alpha-glycosylceramide-pulsed monocyte-derived dendritic cells. J Immunol. 2000 May 1;164(9):4458–4464. doi: 10.4049/jimmunol.164.9.4458. [DOI] [PubMed] [Google Scholar]
  18. Yue F. Y., Geertsen R., Hemmi S., Burg G., Pavlovic J., Laine E., Dummer R. IL-12 directly up-regulates the expression of HLA class I, HLA class II and ICAM-1 on human melanoma cells: a mechanism for its antitumor activity? Eur J Immunol. 1999 Jun;29(6):1762–1773. doi: 10.1002/(SICI)1521-4141(199906)29:06<1762::AID-IMMU1762>3.0.CO;2-F. [DOI] [PubMed] [Google Scholar]

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