In vitro anti-tumour activity of alpha-galactosylceramide-stimulated human invariant Valpha24+NKT cells against melanoma.
alpha-galactosylceramide (KRN 7000, alpha-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 Valpha24+NKT-cells. We hypothesized that human Valpha24+NKT-cells activated by alpha-GalCer might exhibit anti-tumour activity against human melanoma. To investigate this, Valpha24+NKT-cells were generated from the peripheral blood of patients with melanoma after stimulation with alpha-GalCer pulsed monocyte-derived dendritic cells (Mo-DCs). Valpha24+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 Valpha24+NKT-cells (mean +/- SD inhibition of proliferation 63.9 +/- 1.3%). Culture supernatants of activated Valpha24+NKT-cell cultures stimulated with alpha-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-gamma, 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 Valpha24+NKT-cells stimulated by alpha-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 Valpha24+NKT-cells may contribute to clinical anti-tumour effects of alpha-GalCer.
Kikuchi
A
A
Department of Research, The Japanese Red Cross Central Blood Center, 4-1-31 Hiroo, Shibuya-ku, Tokyo, 150-0012, Japan.
Nieda
M
M
Schmidt
C
C
Koezuka
Y
Y
Ishihara
S
S
Ishikawa
Y
Y
Tadokoro
K
K
Durrant
S
S
Boyd
A
A
Juji
T
T
Nicol
A
A
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division; D005699:Galactosylceramides / Q000494:pharmacology*; D006801:Humans; D007111:Immunity, Cellular; D007167:Immunotherapy / Q000379:methods*; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism / Q000627:therapeutic use; D018664:Interleukin-12 / Q000378:metabolism / Q000627:therapeutic use; D015847:Interleukin-4 / Q000378:metabolism / Q000627:therapeutic use; D007694:Killer Cells, Natural / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D008213:Lymphocyte Activation; D008545:Melanoma / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D010641:Phenotype; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000276:Adjuvants, Immunologic; D000970:Antineoplastic Agents; D005699:Galactosylceramides; D016753:Interleukin-10; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma; C103873:KRN 7000