Chamoto Kenji, Tsuji Takemasa, Funamoto Hiromi, Kosaka Akemi, Matsuzaki Junko, Sato Takeshi, Abe Hiroyuki, Fujio Keishi, Yamamoto Kazuhiko, Kitamura Toshio, Takeshima Tsuguhide, Togashi Yuji, Nishimura Takashi
Division of Immunoregulation, Section of Disease Control, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
Cancer Res. 2004 Jan 1;64(1):386-90. doi: 10.1158/0008-5472.can-03-2596.
Adoptive immunotherapy using antigen-specific T-helper type 1 (Th1) cells has been considered as a potential strategy for tumor immunotherapy. However, its application to tumor immunotherapy has been hampered by difficulties in expanding tumor-specific Th1 cells from tumor-bearing hosts. Here, we have developed an efficient protocol for preparing mouse antigen-specific Th1 cells from nonspecifically activated Th cells after retroviral transfer of T-cell receptor (TCR)-alpha and TCR-beta genes. We demonstrate that Th1 cells transduced with the TCR-alpha and -beta genes from the I-A(d)-restricted ovalbumin (OVA)(323-339)-specific T-cell clone DO11.10 produce IFN-gamma but not interleukin-4 in response to stimulation with OVA(323-339) peptides or A20 B lymphoma (A20-OVA) cells expressing OVA as a model tumor antigen. TCR-transduced Th1 cells also exhibited cytotoxicity against tumor cells in an antigen-specific manner. Moreover, adoptive transfer of TCR-transduced Th1 cells, but not mock-transduced Th1 cells, exhibited potent antitumor activity in vivo and, when combined with cyclophosphamide treatment, completely eradicated established tumor masses. Thus, TCR-transduced Th1 cells are a promising alternative for the development of effective adoptive immunotherapies.
采用抗原特异性1型辅助性T细胞（Th1）进行过继性免疫治疗被认为是肿瘤免疫治疗的一种潜在策略。然而，从荷瘤宿主中扩增肿瘤特异性Th1细胞存在困难，这阻碍了其在肿瘤免疫治疗中的应用。在此，我们开发了一种高效方案，可在逆转录病毒转导T细胞受体（TCR）-α和TCR-β基因后，从非特异性激活的Th细胞制备小鼠抗原特异性Th1细胞。我们证明，用来自I-A(d)限制性卵清蛋白（OVA）（323-339）特异性T细胞克隆DO11.10的TCR-α和-β基因转导的Th1细胞，在受到OVA（323-339）肽或表达OVA作为模型肿瘤抗原的A20 B淋巴瘤（A20-OVA）细胞刺激时，产生干扰素-γ但不产生白细胞介素-4。TCR转导的Th1细胞还以抗原特异性方式表现出对肿瘤细胞的细胞毒性。此外，TCR转导的Th1细胞而非模拟转导的Th1细胞的过继性转移在体内表现出强大的抗肿瘤活性，并且与环磷酰胺治疗联合使用时，能完全根除已形成的肿瘤块。因此，TCR转导的Th1细胞是开发有效过继性免疫疗法的一种有前景的替代方案。
