Cytotoxic effects of gammadelta T cells expanded ex vivo by a third generation bisphosphonate for cancer immunotherapy.
Nitrogen containing-bisphosphonates (N-BPs), widely used to treat bone diseases, have direct antitumor effects via the inactivation of Ras proteins. In addition to the direct antitumor activities, N-BPs expand gammadeltaT cells, which exhibit major histocompatibility complex-unrestricted lytic activity. BPs accumulate intermediate metabolites which may be tumor antigens in target cells. The purpose of our study was to clarify the cytotoxicity of gammadelta T cells expanded ex vivo by the most potent N-BP, zoledronate (ZOL). Especially, we focused on the importance of pretreatment against target cells also with ZOL; 1 microM ZOL plus IL-2 increased the absolute number of gammadeltaT cells 298-768 fold for 14 days incubation. The small cell lung cancer and fibrosarcoma cell lines pretreated with 5 microM ZOL showed a marked increase in sensitivity to lysis by gammadeltaT cells. While, untreated cell lines were much less sensitive to lysis by gdT cells. Video microscopy clearly demonstrated that gammadeltaT cells killed target cells pre-treated with ZOL within 3 hr. Pretreatment with 80 microg/kg ZOL also significantly enhanced the antitumor activity of gammadeltaT cells in mice xenografted with SBC-5 cells. These findings show that ZOL significantly stimulated the proliferation of gammadeltaT cells and that gammadeltaT cells required pre-treatment with ZOL for cytotoxic activity against target cells.
Sato
Kiyoshi
K
Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, Kyoto, Japan.
Kimura
Shinya
S
Segawa
Hidekazu
H
Yokota
Asumi
A
Matsumoto
Seiji
S
Kuroda
Junya
J
Nogawa
Masaki
M
Yuasa
Takeshi
T
Kiyono
Yasushi
Y
Wada
Hiromi
H
Maekawa
Taira
T
D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic; D004164:Diphosphonates / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000628:therapy*; D011897:Random Allocation; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D000077211:Zoledronic Acid
D004164:Diphosphonates; D007093:Imidazoles; D016692:Receptors, Antigen, T-Cell, gamma-delta; D000077211:Zoledronic Acid