Generation of tumor-specific, HLA class I-restricted human Th1 and Tc1 cells by cell engineering with tumor peptide-specific T-cell receptor genes
Generation of tumor-specific, HLA class I-restricted human Th1 and Tc1 cells by cell engineering with tumor peptide-specific T-cell receptor genes
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DOI：
10.1182/blood-2004-09-3663
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发表时间：
2005-07-15
期刊：
影响因子：
20.3
通讯作者：
Nishimura, T
中科院分区：
文献类型：
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作者：
Tsuji, T;Yasukawa, M;Nishimura, T
肿瘤抗原特异性的CD4(+)和CD8(+)T细胞，特别是产生干扰素-γ(IFN-γ)的1型辅助性T细胞(Th1)和1型细胞毒性T细胞(Tc1)在肿瘤清除中起着至关重要的作用。使用肿瘤特异性Th1和Tc1细胞过继转移是一种很有前途的肿瘤免疫治疗策略。然而，由于从肿瘤患者中产生肿瘤特异性Th1细胞的困难，它的临床应用一直受到阻碍。为了克服这个问题，我们开发了一种有效的方法来制备肿瘤特异性Th1和Tc1细胞。从人类白细胞抗原A24限制性的Wilms肿瘤1(WT1)多肽克隆中获得的T细胞受体(TCR)α和β基因被慢病毒转导到多克隆激活的Th1和Tc1细胞。正如预期的那样，TCR基因修饰的Tc1细胞对负载多肽的淋巴母细胞系、WT1基因转导细胞和新分离的同时表达WT1和HLA-A24的白血病细胞具有细胞毒作用和产生干扰素-γ的反应。令人惊讶的是，我们进一步证明，转导了HLAI类限制性TCR基因的Th1细胞也以一种HLAA24受限的方式显示出细胞毒作用和细胞因子的产生。与基因修饰的Tc1细胞相比，Th1细胞除产生干扰素-γ外，还产生大量的白介素2(IL-2)，这有利于诱导抗肿瘤细胞免疫。因此，TCR基因修饰的HILA类I-限制性Th1和Tc1细胞是应用于人类肿瘤过继免疫治疗的有力策略。
Tumor antigen-specific CD4(+) and CD8(+) T lymphocytes, especially interferon-gamma (IFN-gamma)-producing type-1 helper T (Th1) and type-1 cytotoxic T (Tc1) cells, play a crucial role in tumor eradication. Adoptive transfer using tumor-specific Th1 and Tc1 cells is a promising therapeutic strategy for tumor immunotherapy. However, its clinical application has been hampered because of difficulties in generating tumor-specific Th1 cells from patients with tumors. To overcome this problem, we have developed an efficient method to prepare tumor-specific Th1 and Tc1 cells. T-cell receptor (TCR) alpha and beta genes obtained from an HLA-A24-restricted, Wilms tumor 1 (WT1) peptide-specific Tc clone were lentivirally transduced to polyclonally activated Th1 and Tc1 cells. As expected, TCR gene-modified Tc1 cells showed cytotoxicity and IFN-gamma production in response to peptide-loaded lymphoblastoid cell lines, WT1 gene-transduced cells, and freshly isolated leukemia cells expressing both WT1 and HLA-A24. Surprisingly, we further demonstrated that Th1 cells transduced with HLA-class I-restricted TCR genes also showed both cytotoxicity and cytokine production in an HLA-A24-restricted manner. In contrast to gene-modified Tc1 cells, Th1 cells produced high amounts of interleukin-2 (IL-2) in addition to IFN-gamma, which is beneficial for induction of antitumor cellular immunity. Thus, TCR gene-modified HILA-class I-restricted Th1 and Tc1 cells are a powerful strategy for the application to adoptive immunotherapy of human cancer.