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Cytotoxic effects of γδ T cells expanded ex vivo by a third generation bisphosphonate for cancer immunotherapy
Author(s) -
Sato Kiyoshi,
Kimura Shinya,
Segawa Hidekazu,
Yokota Asumi,
Matsumoto Seiji,
Kuroda Junya,
Nogawa Masaki,
Yuasa Takeshi,
Kiyono Yasushi,
Wada Hiromi,
Maekawa Taira
Publication year - 2005
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.20987
Subject(s) - cytotoxic t cell , cytotoxicity , cancer research , ex vivo , antigen , chemistry , fibrosarcoma , microbiology and biotechnology , cell culture , cancer cell , in vivo , t cell , immunology , biology , immune system , in vitro , medicine , cancer , biochemistry , pathology , genetics
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 gdγδT 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 gdγδ 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 mμM ZOL plus IL‐2 increased the absolute number of gdγδT cells 298–768 fold for 14 days incubation. The small cell lung cancer and fibrosarcoma cell lines pretreated with 5 mμM ZOL showed a marked increase in sensitivity to lysis by gdγδT cells. While, untreated cell lines were much less sensitive to lysis by gdT cells. Video microscopy clearly demonstrated that gdγδT cells killed target cells pre‐treated with ZOL within 3 hr. Pretreatment with 80 mμg/kg ZOL also significantly enhanced the antitumor activity of gdγδT cells in mice xenografted with SBC‐5 cells. These findings show that ZOL significantly stimulated the proliferation of gdγδT cells and that gdγδT cells required pre‐treatment with ZOL for cytotoxic activity against target cells. © 2005 Wiley‐Liss, Inc.