Rapid αβ TCR-mediated responses in γδ T cells transduced with cancer-specific TCR genes
Rapid αβ TCR-mediated responses in γδ T cells transduced with cancer-specific TCR genes
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DOI：
10.1038/gt.2009.6
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发表时间：
2009-05-01
期刊：
影响因子：
5.1
通讯作者：
Shiku, H.
中科院分区：
文献类型：
--
作者：
Hiasa, A.;Nishikawa, H.;Shiku, H.
体外培养的T细胞的连续性T细胞转移源自具有天然发展的免疫应答的癌症患者，作为免疫治疗方法已经取得了一些成功，尽管只有有限数量的患者显示出自发免疫应答。寻找替代方法，例如癌症特异性T细胞受体（TCR）基因转移，以制备足够数量的抗原特异性T细胞是过继性T细胞治疗领域的重要问题。考虑到α β TCR转移到其他α β T细胞的固有缺点，即可能形成具有内源性α或β TCR的混合TCR异二聚体，我们采用γ δ T细胞作为癌症特异性TCR的逆转录病毒转移的靶标，并检查γ δ T细胞是否可用作TCR转移的替代群体。尽管从MAGE-A4（143-151）-特异性ab CD 8（+）细胞毒性T淋巴细胞（CTL）克隆分离的单独具有TCR α β基因的γ δ T细胞的逆转录病毒转导由于缺乏CD 8辅助受体而不能提供足够的亲和力来识别主要组织相容性（MHC）-肽复合物，用TCR α β和CD 8 α β基因共转导的γ δ T细胞获得针对肿瘤细胞的细胞毒性，并以α β和γ δ TCR依赖性方式产生细胞因子。此外，与传统的α β T细胞相比，通过ab TCR或gd TCR刺激的α β TCR和CD 8转导的gd T细胞对靶细胞迅速应答，使人联想到γ δ T细胞。我们提出α β TCR转导的gd T细胞作为过继性T细胞转移的替代策略。Gene Therapy（2009）16，620-628; doi：10.1038/gt.2009.6; 2009年2月26日在线发表
Adoptive T-cell transfer of in vitro cultured T cells derived from cancer patients with naturally developed immune responses has met with some success as an immunotherapeutic approach, although only a limited number of patients showed spontaneous immune responses. To find alternative ways, such as cancer-specific T-cell receptor (TCR) gene transfer, in preparation for sufficient numbers of antigen-specific T cells is an important issue in the field of adoptive T-cell therapy. Given the inherent disadvantage of alpha beta TCR transfer to other alpha beta T cells, namely the possible formation of mixed TCR heterodimers with endogenous alpha or beta TCR, we employed gamma delta T cells as a target for retroviral transfer of cancer-specific TCR and examined whether gamma delta T cells were useful as an alternative population for TCR transfer. Although retroviral transduction to gamma delta T cells with TCR alpha beta genes alone, isolated from a MAGE-A4(143-151)-specific ab CD8(+) cytotoxic T lymphocyte (CTL) clone, did not provide sufficient affinity to recognize major histocompatibility (MHC)-peptide complexes due to the lack of CD8 co-receptor, gamma delta T cells co-transduced with TCR alpha beta and CD8 alpha beta genes acquired cytotoxicity against tumor cells and produced cytokines in both alpha beta- and gamma delta- TCR-dependent manners. Furthermore, alpha beta TCR and CD8-transduced gd T cells, stimulated either through ab TCR or gd TCR, rapidly responded to target cells compared with conventional alpha beta T cells, reminiscent of gamma delta T cells. We propose alpha beta TCR-transduced gd T cells as an alternative strategy for adoptive T-cell transfer. Gene Therapy (2009) 16, 620-628; doi: 10.1038/gt.2009.6; published online 26 February 2009