Characterization of tumor reactivity of human Vγ9Vδ2 yδ T cells in vitro and in SCID mice in vivo
Characterization of tumor reactivity of human Vγ9Vδ2 yδ T cells in vitro and in SCID mice in vivo
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DOI：
10.4049/jimmunol.173.11.6767
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发表时间：
2004-12-01
影响因子：
4.4
通讯作者：
Zöller, M
中科院分区：
文献类型：
--
作者：
Kabelitz, D;Wesch, D;Zöller, M
人V γ 9 V δ 2 γ δ T细胞被细菌磷酸化抗原和氨基二膦酸盐选择性激活，并对各种肿瘤细胞发挥有效的细胞毒性。在这项研究中，我们已经确定了γ δ T细胞系的细胞毒性反应，建立从健康供体刺激与氨基二膦酸阿仑膦酸钠对黑色素瘤MeWo和胰腺癌Colo 357和PancTu 1线在体外和体内过继转移到SCID小鼠。当γ δ效应细胞用磷酸化抗原预活化时，所有肿瘤细胞的溶解增强。MeWo的识别是TCR依赖性的，如抗TCR Ab阻断所示，而抗TCR Ab仅抑制磷酸化抗原介导的Colo 357和PancTu 1裂解的增加，但不抑制基础裂解。此外，Colo 357的裂解，而不是MeWo或PancTu 1的裂解，被泛半胱天冬酶抑制剂zVAD完全抑制，表明γ δ T细胞/肿瘤细胞相互作用中涉及的不同识别和效应机制。转移到SCID小鼠后，阿仑膦酸钠激活的γ δ T细胞与IL-2和阿仑膦酸钠一起给予，显着延长了接种人肿瘤细胞的SCID小鼠的生存期。因此，当在30天内重复给予γ δ T细胞5次时，获得了最佳结果。使用该方案，人γ δ T细胞将接种MeWo黑色素瘤的小鼠的平均存活时间从28.5天延长至87.3天（p < 0.0001），并且在PancTu 1腺癌的情况下从23.0天延长至48.4天（p < 0.0001）。我们的结论是，一个有效的γ δ T细胞为基础的免疫治疗可能需要激活内源性γ δ T细胞与氨基二膦酸盐（或磷抗原）和IL-2，然后过继转移的体外扩增的γ δ T细胞。
Human Vgamma9Vdelta2 gammadelta T cells are selectively activated by bacterial phosphoantigens and aminobisphosphonates and exert potent cytotoxicity toward various tumor cells. In this study we have characterized the cytotoxic reactivity of gammadelta T cell lines established from healthy donors by stimulation with aminobisphosphonate alendronate toward melanoma MeWo and pancreatic adenocarcinomas Colo357 and PancTu1 lines in vitro and in vivo upon adoptive transfer into SCID mice. Lysis of all tumor cells was enhanced when gammadelta effector cells were preactivated with phosphoantigens. Recognition of MeWo was TCR dependent, as shown by anti-TCR Ab blockade, whereas only the phosphoantigen-mediated increased, but not the basal, lysis of Colo357 and PancTu1 was inhibited by anti-TCR Ab. Furthermore, lysis of Colo357, but not that of MeWo or PancTu1, was completely inhibited by the pan-caspase inhibitor zVAD, indicating different recognition and effector mechanisms involved in the gammadelta T cell/tumor cell interactions. Upon transfer into SCID mice, alendronate-activated gammadelta T cells given together with IL-2 and alendronate significantly prolonged the survival of SCID mice inoculated with human tumor cells. The best results were thus obtained when gammadelta T cells were repetitively given five times over a period of 30 days. With this protocol, human gammadelta T cells prolonged the mean survival of mice inoculated with MeWo melanoma from 28.5 to 87.3 days (p < 0.0001) and in the case of PancTu1 adenocarcinoma from 23.0 to 48.4 days (p < 0.0001). We conclude that an effective gammadelta T cell-based immunotherapy might require activation of endogenous gammadelta T cells with aminobisphosphonate (or phosphoantigen) and IL-2, followed by adoptive transfer of in vitro expanded gammadelta T cells.