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 www.bjcancer.com
Similar content being viewed by others
Article PDF
Change history
16 November 2011
This paper was modified 12 months after initial publication to switch to Creative Commons licence terms, as noted at publication
References
Azzoni, L, Zatsepina, O, Abebe, B, Bennett, IM, Kanakaraj, P & Perussia, B (1998). 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, 161, 3493–3500.
Bezouska, K, Yuen, CT, O’Brien, J, Childs, RA, Chai, W, Lawson, AM, Drbal, K, Fiserova, A, Pospisil, M & Feizi, T (1994). Oligosaccharide ligands for NKR-P1 protein activate NK cells and cytotoxicity (published erratum appears in Nature 1996 Apr 11 380(6574) 559). Nature, 372, 150–157.
Burdin, N, Brossay, L & Kronenberg, M (1999). Immunization with alpha-galactosylceramide polarizes CD1-reactive NK T cells towards Th2 cytokine synthesis. Eur J Immunol, 29, 2014–2025.
Calabi, F & Bradbury, A (1991). The CD1 system. Tissue Antigens, 37, 1–9.
Couedel, C, Peyrat, MA, Brossay, L, Koezuka, Y, Porcelli, SA, Davodeau, F & Bonneville, M (1998). Diverse CD1d-restricted reactivity patterns of human T cells bearing ‘invariant’ AV24BV11 TCR. Eur J Immunol, 28, 4391–4397.
Cui, J, Shin, T, Kawano, T, Sato, H, Kondo, E, Toura, I, Kaneko, Y, Koseki, H, Kanno, M & Taniguchi, M (1997). Requirement for Valpha14 NKT cells in IL-12-mediated rejection of tumours. Science, 278, 1623–1626.
Dellabona, P, Padovan, E, Casorati, G, Brockhaus, M & Lanzavecchia, A (1994). 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, 180, 1171–1176.
Fujimoto, T, O’Donnell, MA, Szilvasi, A, Yang, H & Duda, RB (1996). Bacillus Calmette-Guerin 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, 42, 280–284.
Gillis, S & Williams, DE (1998). Cytokine therapy: lessons learned and future challenges (editorial). Curr Opin Immunol, 10, 501–503.
Kawano, T, Cui, J, Koezuka, Y, Toura, I, Kaneko, Y, Sato, H, Kondo, E, Harada, M, Koseki, H, Nakayama, T, Tanaka, Y & Taniguchi, M (1998). Natural killer-like nonspecific tumour cell lysis mediated by specific ligand-activated Valpha14 NKT cells. Proc Natl Acad Sci USA, 95, 5690–5693.
Kawano, T, Cui, J, Koezuka, Y, Toura, I, Kaneko, Y, Motoki, K, Ueno, H, Nakagawa, R, Sato, H, Kondo, E, Koseki, H & Taniguchi, M (1997). CD1d-restricted and TCR-mediated activation of valpha14 NKT cells by glycosylceramides. Science, 278, 1626–1629.
Kawano, T, Nakayama, T, Kamada, N, Kaneko, Y, Harada, M, Ogura, N, Akutsu, Y, Motohashi, S, Iizasa, T, Endo, H, Fujisawa, T, Shinkai, H & Taniguchi, M (1999). Antitumour cytotoxicity mediated by ligand-activated human V alpha24 NKT cells. Cancer Res, 59, 5102–5105.
Kitamura, H, Iwakabe, K, Yahata, T, Nishimura, S, Ohta, A, Ohmi, Y, Sato, M, Takeda, K, Okumura, K, Van Kaer, L, Kawano, T, Taniguchi, M & Nishimura, T (1999). 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, 189, 1121–1128.
Kobayashi, E, Motoki, K, Uchida, T, Fukushima, H & Koezuka, Y (1995). KRN7000, a novel immunomodulator, and its antitumour activities. Oncol Res, 7, 529–534.
Nicol, AJ, Nieda, M, Koezuka, Y, Porcelli, S, Suzuki, K, Tadokoro, K, Durrant, S & Juji, T (2000). Human invariant Vα24+ NKT cells activated by α-GalactosylCeramide (KRN7000) have cytotoxic antitumour activity through mechanisms distinct from T cells and NK cells. Immunology, 99, 229–234.
Nieda, M, Nicol, A, Koezuka, Y, Kikuchi, A, Takahashi, T, Nakamura, H, Furukawa, H, Yabe, T, Ishikawa, Y, Tadokoro, K & Juji, T (1999). Activation of human Valpha24NKT cells by alpha-glycosylceramide in a CD1d-restricted and Valpha24TCR-mediated manner. Hum Immunol, 60, 10–19.
Takahashi, T, Nieda, M, Koezuka, Y, Nicol, A, Porcelli, SA, Ishikawa, Y, Tadokoro, K, Hirai, H & Juji, T (2000). Analysis of human Va24+CD4+NKT cells activated by α-glycosylceramide-pulsed monocyte-derived dendritic cells. J of Immunology, 164, 4458–4464.
Yue, FY, Geertsen, R, Hemm, S, Burg, G, Pavlovic, J, Laine, E & Dummer, R (1999). 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 antitumour activity?. Eur J Immunol, 29, 1762–1773.
Author information
Authors and Affiliations
Rights and permissions
From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
About this article
Cite this article
Kikuchi, A., Nieda, M., Schmidt, C. et al. In vitro anti-tumour activity of α-galactosylceramide-stimulated human invariant Vα24+NKT cells against melanoma. Br J Cancer 85, 741–746 (2001). https://doi.org/10.1054/bjoc.2001.1973
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1054/bjoc.2001.1973
Keywords
This article is cited by
-
Accumulation of invariant NKT cells with increased IFN-γ production in persistent high-risk HPV-infected high-grade cervical intraepithelial neoplasia
Diagnostic Pathology (2015)
-
Small-molecule Bcl-2 inhibitors sensitise tumour cells to immune-mediated destruction
British Journal of Cancer (2007)
-
HLA class I and class II frequencies in patients with cutaneous malignant melanoma from southeastern Spain: the role of HLA-C in disease prognosis
Immunogenetics (2006)
-
Modulation of human Vα24+Vβ11+ NKT cells by age, malignancy and conventional anticancer therapies
British Journal of Cancer (2004)
-
Identification of membrane-type matrix metalloproteinase-1 as a target of the β-catenin/Tcf4 complex in human colorectal cancers
Oncogene (2002)