Cytotoxic human peripheral blood-derived γδT cells kill glioblastoma cell lines: implications for cell-based immunotherapy for patients with glioblastoma.
Glioblastoma (GBM) is a highly aggressive brain tumor for which novel therapeutic approaches, such as immunotherapy, are urgently needed. Zoledronate (ZOL), an inhibitor of osteoclastic activity, is known to stimulate peripheral blood-derived γδT cells and sensitize tumors to γδT cell-mediated killing. To investigate the feasibility of γδT cell-based immunotherapy for patients with GBM, we focused on the killing of GBM cell lines by γδT cells and the molecular mechanisms involved in these cell-cell interactions. Peripheral blood mononuclear cells were expanded in ZOL and interleukin (IL)-2 for 14 days, and γδT cells were enriched in the expanded cells by the immunomagnetic depletion of αβT cells. Gliomas are resistant to NK cells but susceptible to lymphokine-activated killer cells and some cytotoxic T lymphocytes. When the γδT cell-mediated killing of three GBM cell lines (U87MG, U138MG and A172 cells) and an NK-sensitive leukemia cell line (K562 cells) were tested, 32% U87MG, 15% U138MG, 1% A172, and 50% K562 cells were killed at an effector:target ratio of 5:1. The γδT cell-mediated killing of all three GBM cell lines was significantly enhanced by ZOL and this ZOL-enhanced killing was blocked by an anti-T cell receptor (TcR) antibody. These results indicated that TcR γδ is crucial for the recognition of ZOL-treated GBM cells by γδT cells. Since the low level killing of GBM cells by the γδT cells was enhanced by ZOL, γδT cell-targeting therapy in combination with ZOL treatment could be effective for patients with GBM.
Department of Neurosurgery, Nara Medical University School of Medicine, 840, Shijocho, Kashihara, Nara, 634-8522, Japan, nakazawa@naramed-u.ac.jp.
Tsutomu
T
Nakazawa
Mitsutoshi
M
Nakamura
Young Soo
YS
Park
Yasushi
Y
Motoyama
Yasuo
Y
Hironaka
Fumihiko
F
Nishimura
Ichiro
I
Nakagawa
Shuichi
S
Yamada
Ryosuke
R
Matsuda
Kentaro
K
Tamura
Tadashi
T
Sugimoto
Yasuhiro
Y
Takeshima
Akiko
A
Marutani
Takahiro
T
Tsujimura
Noriko
N
Ouji
Yukiteru
Y
Ouji
Masahide
M
Yoshikawa
Hiroyuki
H
Nakase
D000704:Analysis of Variance; D015703:Antigens, CD / Q000378:metabolism; D050071:Bone Density Conservation Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D004164:Diphosphonates / Q000494:pharmacology; D005434:Flow Cytometry; D005452:Fluoresceins / Q000378:metabolism; D005909:Glioblastoma / Q000276:immunology / Q000473:pathology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology* / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology*; D013997:Time Factors; D000077211:Zoledronic Acid
D015703:Antigens, CD; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D005452:Fluoresceins; D007093:Imidazoles; D016692:Receptors, Antigen, T-Cell, gamma-delta; C085925:calcein AM; D000077211:Zoledronic Acid