Induction of γδT Cells Using Zoledronate Plus Interleukin-2 in Patients with Metastatic Cancer

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タイトル ( eng )
Induction of γδT Cells Using Zoledronate Plus Interleukin-2 in Patients with Metastatic Cancer
作成者
Nagamine Ichiro
Yamaguchi Yoshiyuki
Ohara Masahiro
Ikeda Takuhiro
収録物名
Hiroshima Journal of Medical Sciences
58
1
開始ページ 37
終了ページ 44
収録物識別子
[PISSN] 0018-2052
[EISSN] 2433-7668
[NCID] AA00664312
抄録
A loss of human leukocyte antigen (HLA) expression in clinical tumors is one of their escape mechanisms from immune attack by HLA-restricted effector cells. In this study, the induction of HLA-unrestricted effector cells, γδT cells, using zoledronate (ZOL) and interleukin (IL)-2 in vitro was investigated in patients with metastatic cancer. Peripheral blood mononuclear cells (PBMCs) from 10 cancer patients (8 colorectal and 2 esophageal) with multiple metastases and ascites lymphocytes from 3 cancer patients (1 gastric and 2 colorectal) were stimulated with varied concentrations of ZOL plus 100 U/ml IL-2 for 48 hr followed by culturing with IL-2 alone for 12 days. Lymphocyte proliferative responses were determined using 3H-TdR uptakes and interferon (IFN)-γ production was evaluated using enzyme-linked immunosorbent assay. Surface phenotyping was performed using flow cytometry. Cytotoxic activity of effector cells was determined using 51Cr-releasing assay.
It was found that proliferative responses of PBMCs were significantly stimulated with ZOL plus IL-2 when compared with IL-2 alone, showing 200 to 500-fold expansions for 2 weeks, although ZOL alone induced no response. The optimal concentration of ZOL was 1-5 μM. Ascites lymphocytes could also be stimulated with ZOL plus IL-2. The proliferative responses were remarkable in patients whose PBMCs could produce high levels ofIFN-γ during an initial 48-hr stimulation using ZOL plus IL-2. Removal of an adherent cell fraction before the induction augmented the proliferative responses in patients who otherwise had low-grade proliferative responses. Generated cells comprising approximately 90 or 20% in PBMCs from healthy donors or cancer patients, respectively, expressed γδ-type T-cell receptor. γδT cells showed high cytotoxic activity against CD166-positive TE12 and TE13 cancer cells but not against CD166-negative MKN45 cells. The cytotoxic activity against TE13 cells was augmented when target cells were pre-treated overnight with ZOL.
These results suggest that ZOL in the presence of IL-2 can efficiently stimulate the proliferation of γδT cells, which have cytotoxic properties against cancer cells. The use of zoledronate-activated killer (ZAK) cells should be encouraged in possible adoptive immunotherapy trials for patients with incurable cancer.
著者キーワード
γδT cells
Zoledronate
Interleukin-2
Adoptive immunotherapy
Cancer
NDC分類
医学 [ 490 ]
言語
英語
資源タイプ 紀要論文
出版者
Hiroshima University Medical Press
発行日 2009-03
権利情報
(c) Hiroshima University Medical Press.
出版タイプ Version of Record(出版社版。早期公開を含む)
アクセス権 オープンアクセス
収録物識別子
[ISSN] 0018-2052
[NCID] AA00664312