1] Cancer Research Unit, Research Division, Departments of Oncology, Saskatchewan Cancer Agency, University of Saskatchewan, Saskatoon, Saskatchewan, Canada [2] Department of Oncology, the First Affiliated Hospital of Soochow University, Suzhou, China.
Cancer Gene Ther. 2013 Oct;20(10):590-8. doi: 10.1038/cgt.2013.60. Epub 2013 Sep 20.
One of the major obstacles in human epidermal growth factor receptor (HER)-2/neu-specific trastuzumab immunotherapy of HER2/neu-positive breast cancer is the development of trastuzumab resistance, warranting the search for other therapeutic strategies. Although dendritic cell (DC) vaccines have been extensively applied in clinical trials for cancer treatment, the vaccination efficacy is still limited, mostly because DC vaccines are not sufficient to break tumor-associated antigen-specific self-immune tolerance in cancer patients. P30 (FNNFTVSFWLRVPKVSASHLE) derived from tetanus toxin is a universally potent CD4(+) T helper epitope capable of enhancing CD8(+) cytotoxic T-lymphocyte (CTL) responses. In this study, we constructed two recombinant adenoviral vectors (AdVs), AdVOVA-P30 and AdVHER2/neu-P30, expressing ovalbumin (OVA)-P30 and HER2/neu-P30. In order to enhance DC vaccine efficacy, we transfected mouse bone marrow (BM)-derived DCs with AdVOVA-P30 and AdVHER2/neu-P30 to generate engineered DCOVA-P30 and DCHER2/neu-P30 vaccines, respectively. We, then, compared CD4(+) and CD8(+) T-cell responses and antitumor immunity derived from DCOVA-P30 and DCHER2/neu-P30 vaccination in wild-type C57BL/6 and transgenic FVBneuN mice, respectively. We demonstrate that engineered DCOVA-P30 vaccine stimulates more efficient CD4(+) and CD8(+) T-cell responses than DCOVA in C57BL/6 mice. Interestingly, the increased DCOVA-P30-induced CTL responses are mainly contributed by enhanced CD4(+) T-cell-stimulated CTL proliferation. We show that DCOVA-P30 vaccine also stimulates more efficient therapeutic immunity against OVA-expressing BL6-10OVA melanoma than DCOVA in C57BL/6 mice. In addition, we demonstrate that DCHER2/neu-P30 vaccine stimulates more efficient CD4(+) and CD8(+) T-cell responses and protective immunity against HER2/neu-expressing Tg1-1 breast cancer than DCHER2/neu in transgenic FVBneuN mice with HER2/neu-specific self-immune tolerance. Therefore, the engineered DCHER2/neu-P30 vaccine may provide a new immunotherapy alternative for women with HER2/neu(+) breast cancer, especially for trastuzumab-resistant HER2/neu(+) breast cancer patients.
表皮生长因子受体 (HER)-2/neu 是人表皮生长因子受体的一种，针对其的曲妥珠单抗免疫疗法是治疗 HER2/neu 阳性乳腺癌的主要方法之一，但存在产生曲妥珠单抗耐药性的问题，这就需要寻找其他的治疗策略。树突状细胞 (DC) 疫苗已广泛应用于癌症治疗的临床试验中，但疫苗的疗效仍然有限，这主要是因为 DC 疫苗不足以打破癌症患者中肿瘤相关抗原特异性自身免疫耐受。破伤风类毒素衍生的 P30（FNNFTVSFWLRVPKVSASHLE）是一种普遍有效的 CD4+T 辅助表位，能够增强 CD8+细胞毒性 T 淋巴细胞（CTL）的反应。在本研究中，我们构建了两种重组腺病毒载体（AdV），AdVOVA-P30 和 AdVHER2/neu-P30，分别表达卵清蛋白（OVA）-P30 和 HER2/neu-P30。为了增强 DC 疫苗的疗效，我们分别用 AdVOVA-P30 和 AdVHER2/neu-P30 转染小鼠骨髓（BM）来源的 DC，以生成工程化的 DCOVA-P30 和 DCHER2/neu-P30 疫苗。然后，我们分别在野生型 C57BL/6 和转基因 FVBneuN 小鼠中比较了 DCOVA-P30 和 DCHER2/neu-P30 接种引起的 CD4+和 CD8+T 细胞反应和抗肿瘤免疫。我们证明，与 C57BL/6 小鼠中的 DCOVA 相比，工程化的 DCOVA-P30 疫苗可刺激更有效的 CD4+和 CD8+T 细胞反应。有趣的是，增强的 DCOVA-P30 诱导的 CTL 反应主要归因于增强的 CD4+T 细胞刺激的 CTL 增殖。我们还证明，与 C57BL/6 小鼠中的 DCOVA 相比，DCOVA-P30 疫苗还可刺激更有效的针对表达 OVA 的 BL6-10OVA 黑色素瘤的治疗性免疫。此外，我们证明，与 DCHER2/neu 相比，DCHER2/neu-P30 疫苗在具有 HER2/neu 特异性自身免疫耐受的转基因 FVBneuN 小鼠中可刺激更有效的 CD4+和 CD8+T 细胞反应和针对表达 HER2/neu 的 Tg1-1 乳腺癌的保护性免疫。因此，工程化的 DCHER2/neu-P30 疫苗可能为 HER2/neu（+）乳腺癌患者，特别是曲妥珠单抗耐药的 HER2/neu（+）乳腺癌患者提供新的免疫治疗选择。
