Antimetastatic activity of a preventive cancer vaccine
Antimetastatic activity of a preventive cancer vaccine
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DOI：
10.1158/0008-5472.can-07-2499
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发表时间：
2007-11-15
期刊：
影响因子：
11.2
通讯作者：
Lollini, Pier-Luigi
中科院分区：
文献类型：
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作者：
Nanni, Patrizia;Nicoletti, Giordano;Lollini, Pier-Luigi
保护健康宿主免受肿瘤发展的预防性癌症疫苗的开发留下了这样的疫苗是否也对已建立的肿瘤和转移有效的问题。我们在HER-2/neu转基因小鼠中测试了经证实的预防性抗HER-2/neu疫苗对乳腺癌进展的连续阶段的治疗活性。该疫苗由表达HER-2/neu的转基因乳腺癌细胞和两种佐剂组成：同种异体I类组织相容性抗原和白细胞介素（IL）-12。携带肺微转移的小鼠接种疫苗导致90%的转移发展抑制，而具有初始局部肿瘤的小鼠接种疫苗无效。抗转移反应受到免疫耐受的阻碍，因为转基因小鼠的保护低于对HER-2/neu不耐受的野生型同类小鼠。通过共施用靶向调节性T细胞的抗CD 25单克隆抗体，在转基因小鼠中获得了免疫抑制活性的显著增加，这导致>99%的转移抑制。在转基因小鼠中引发的免疫应答包括肺粒细胞和巨噬细胞的活化以及基于辅助T细胞及其细胞因子（IFN-γ和IL-4）和抗HER-2/neu抗体的全身适应性应答。通过基因敲除小鼠和耗竭抗体对相关抗转移机制的剖析揭示了肿瘤预防（完全依赖于抗HER-2/neu抗体）和转移治疗（不依赖于抗体）之间的主要差异。总之，一种成功开发的癌症免疫预防疫苗对肺转移显示出较强的治疗活性，其由保护性免疫机制介导，与预防原发性乳腺癌发作的免疫机制不同。
The development of prophylactic cancer vaccines that protect healthy hosts from tumor development leaves open the question whether such vaccines are also effective against established tumors and metastases. We tested the therapeutic activity of a proven prophylactic anti-HER-2/neu vaccine against successive stages of mammary carcinoma progression in HER-2/neu transgenic mice. The vaccine consisted of transgenic mammary carcinoma cells expressing HER-2/neu and two adjuvants: allogeneic class I histocompatibility antigens and interleukin (IL)-12. Vaccination of mice bearing lung micrometastases resulted in a 90% inhibition of metastasis development, whereas vaccination of mice with incipient local tumors was ineffective. The antimetastatic response was hampered by immune tolerance, as the protection of transgenic mice was lower than that of wildtype congenics not tolerant to HER-2/neu. A significant gain in immunotherapeutic activity in transgenic mice was obtained through the coadministration of anti-CD25 monoclonal antibody targeting regulatory T cells, which resulted in a >99% inhibition of metastasis. The immune responses elicited in transgenic mice comprised the activation of lung granulocytes and macrophages and of systemic adaptive responses based on helper T cells and their cytokines (IFN-gamma and IL-4) and anti-HER-2/neu antibodies. Dissection of relevant antimetastatic mechanisms by means of knockout mice and of depleting antibodies revealed a major difference between tumor prevention, which was completely dependent on anti-HER-2/neu antibodies, and metastasis therapy, which was antibody independent. In conclusion, a vaccine successfully developed for cancer immunoprevention showed a strong therapeutic activity against lung metastases mediated by protective immune mechanisms distinct from those preventing the onset of primary mammary carcinoma.