Kondo M, Sakuta K, Noguchi A, Ariyoshi N, Sato K, Sato S, Sato K, Hosoi A, Nakajima J, Yoshida Y, Shiraishi K, Nakagawa K, Kakimi K
Department of Immunotherapeutics (Medinet), University of Tokyo Hospital, Tokyo, Japan.
Cytotherapy. 2008;10(8):842-56. doi: 10.1080/14653240802419328.
Human gammadelta T cells can be activated by phospho-antigens and aminobisphosphonates such as zoledronate. Because they can kill tumor cells in a major histocompatibility complex (MHC)-unrestricted manner, adoptive transfer of activated gammadelta T cells may represent a novel cancer immunotherapy. We tested whether gammadelta T cells from advanced cancer patients can be expanded by zoledronate.
Peripheral blood mononuclear cells from healthy donors and patients with advanced non-small cell lung cancer, bone metastatic breast or prostate cancer, or lung metastatic colorectal cancer, were stimulated with zoledronate (5 microM) and interleukin (IL)-2 (1000 IU/mL) for 14 days. The phenotype and function of the expanded gammadelta T-cell populations from healthy donors and cancer patients were compared.
Gammadelta T cells from cancer patients and healthy donors responded to zoledronate equally well in terms of both phenotype and function. gammadelta T cells grew rapidly in vitro and expression of effector molecules, such as interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, perforin, granzyme B, FasL and TRAIL, increased over time. Cytotoxicity peaked on days 12-14, and proliferation continued up to 14 days, during which time>1x10(9) gammadelta T cells could be obtained from a starting sample of 45-70 mL peripheral blood.
Using the agent zoledronate, already widely used in the clinic, we have established that efficient large-scale ex vivo expansion of gammadelta T cells from cancer patients is possible. These cells exert potent cytotoxicity and may be used for autologous cellular immunotherapy of cancer.
人γδT细胞可被磷酸抗抗原和氨基双膦酸盐（如唑来膦酸）激活。由于它们能够以主要组织相容性复合体（MHC）非限制性方式杀伤肿瘤细胞，因此过继转移活化的γδT细胞可能代表一种新型癌症免疫疗法。我们测试了晚期癌症患者的γδT细胞是否能被唑来膦酸扩增。
用唑来膦酸（5微摩尔）和白细胞介素（IL）-2（1000国际单位/毫升）刺激健康供者以及晚期非小细胞肺癌、骨转移性乳腺癌或前列腺癌、肺转移性结直肠癌患者的外周血单个核细胞14天。比较健康供者和癌症患者扩增的γδT细胞群体的表型和功能。
癌症患者和健康供者的γδT细胞在表型和功能方面对唑来膦酸的反应同样良好。γδT细胞在体外快速生长，效应分子如干扰素（IFN）-γ、肿瘤坏死因子（TNF）-α、穿孔素、颗粒酶B、FasL和TRAIL的表达随时间增加。细胞毒性在第12 - 14天达到峰值，增殖持续至14天，在此期间，从45 - 70毫升外周血的起始样本中可获得>1×10⁹个γδT细胞。
使用已在临床上广泛应用的药物唑来膦酸，我们已证实从癌症患者高效大规模体外扩增γδT细胞是可行的。这些细胞具有强大的细胞毒性，可用于癌症的自体细胞免疫治疗。
