Department of Pathology, VU University Medical Center, de Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
J Transl Med. 2011 Sep 5;9:147. doi: 10.1186/1479-5876-9-147.
Infection with high risk Human Papilloma Virus (HPV) is associated with cancer of the cervix, vagina, penis, vulva, anus and some cases of head and neck carcinomas. The HPV derived oncoproteins E6 and E7 are constitutively expressed in tumor cells and therefore potential targets for T cell mediated adoptive immunotherapy. Effective immunotherapy is dependent on the presence of both CD4+ and CD8+ T cells. However, low precursor frequencies of HPV16 specific T cells in patients and healthy donors hampers routine isolation of these cells for adoptive transfer purposes. An alternative to generate HPV specific CD4+ and CD8+ T cells is TCR gene transfer.
HPV specific CD4+ T cells were generated using either a MHC class I or MHC class II restricted TCR (from clones A9 and 24.101 respectively) directed against HPV16 antigens. Functional analysis was performed by interferon-γ secretion, proliferation and cytokine production assays.
Introduction of HPV16 specific TCRs into blood derived CD4+ recipient T cells resulted in recognition of the relevant HPV16 epitope as determined by IFN-γ secretion. Importantly, we also show recognition of the endogenously processed and HLA-DP1 presented HPV16E6 epitope by 24.101 TCR transgenic CD4+ T cells and recognition of the HLA-A2 presented HPV16E7 epitope by A9 TCR transgenic CD4+ T cells.
Our data indicate that TCR transfer is feasible as an alternative strategy to generate human HPV16 specific CD4+ T helper cells for the treatment of patients suffering from cervical cancer and other HPV16 induced malignancies.
高危型人乳头瘤病毒（HPV）感染与宫颈癌、阴道癌、阴茎癌、外阴癌、肛门癌以及部分头颈部癌有关。HPV 衍生的癌蛋白 E6 和 E7 在肿瘤细胞中持续表达，因此是 T 细胞介导的过继免疫治疗的潜在靶点。有效的免疫治疗依赖于 CD4+和 CD8+T 细胞的存在。然而，患者和健康供体中 HPV16 特异性 T 细胞的前体频率较低，阻碍了这些细胞的常规分离，以用于过继转移。生成 HPV 特异性 CD4+和 CD8+T 细胞的替代方法是 TCR 基因转移。
使用针对 HPV16 抗原的 MHC Ⅰ类或 MHC Ⅱ类受限 TCR（分别来自克隆 A9 和 24.101）生成 HPV 特异性 CD4+T 细胞。通过干扰素-γ分泌、增殖和细胞因子产生测定进行功能分析。
将 HPV16 特异性 TCR 导入血液衍生的 CD4+受体 T 细胞中，导致通过 IFN-γ 分泌识别相关 HPV16 表位。重要的是，我们还显示 24.101 TCR 转基因 CD4+T 细胞识别内源性加工和 HLA-DP1 呈递的 HPV16E6 表位，以及 A9 TCR 转基因 CD4+T 细胞识别 HLA-A2 呈递的 HPV16E7 表位。
我们的数据表明，TCR 转移是可行的，作为一种替代策略，用于生成人类 HPV16 特异性 CD4+辅助性 T 细胞，用于治疗患有宫颈癌和其他 HPV16 诱导的恶性肿瘤的患者。
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