Vaccination with dendritic cells pulsed with apoptotic tumors in combination with Anti-OX40 and Anti-4-1BB monoclonal antibodies induces T cell-mediated protective immunity in Her-2/neu transgenic mice
Vaccination with dendritic cells pulsed with apoptotic tumors in combination with Anti-OX40 and Anti-4-1BB monoclonal antibodies induces T cell-mediated protective immunity in Her-2/neu transgenic mice
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DOI：
10.1002/ijc.21098
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发表时间：
2005-10-10
影响因子：
6.4
通讯作者：
Lustgarten, J
中科院分区：
文献类型：
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作者：
Cuadros, C;Dominguez, AL;Lustgarten, J
肿瘤细胞表达肿瘤相关抗原（TAA），其可作为免疫系统的靶标。然而，大多数TAA是正常细胞基因的过表达产物;因此，自身耐受机制阻碍了它们用于诱导有效的抗肿瘤反应。一种这样的正常自身蛋白是生长因子受体Her-2/neu，其在人类所有乳腺癌的25-35%中过表达。在以前的研究中，我们已经证明，Her-2/neu小鼠是功能耐受neu抗原，只包含一个低亲和力的T细胞库neu抗原。然而，这种残留的低亲和力T细胞库具有抗肿瘤活性。在这项研究中，我们比较了Her-2/neu小鼠免疫树突状细胞（DC）与可溶性neu蛋白和凋亡肿瘤细胞的免疫反应。抗肿瘤反应的分析表明，用Her-2/neu抗原脉冲的DC接种Her-2/neu小鼠延缓肿瘤生长;然而，用凋亡肿瘤细胞脉冲的DC接种Her-2/neu小鼠诱导更强的抗肿瘤作用。多次免疫接种联合共刺激激动剂抗OX 40或抗4-1BB单克隆抗体显著增强了这些小鼠的免疫应答，如果肿瘤负荷较小，则导致完全肿瘤排斥，而肿瘤负荷较大时则导致肿瘤显著减少。这些结果对肿瘤疫苗接种策略的设计具有重要意义，表明使用刺激广泛免疫应答的疫苗与作为免疫调节剂的共刺激分子组合可以显着改善耐受宿主的抗肿瘤免疫应答。(C)2005 Wiley-Liss，Inc.
Tumor cells express tumor-associated antigens (TAAs), which can serve as targets for the immune system. However, the majority of TAAs are overexpressed products of normal cellular genes; as such, self-tolerance mechanisms have hindered their use for the induction of effective antitumor responses. One such normal self-protein is the growth factor receptor Her-2/neu, which is overexpressed in 25-35% of all mammary carcinomas in humans. In previous studies, we have demonstrated that Her-2/neu mice are functionally tolerant to neu antigens and contain only a low avidity T-cell repertoire to neu antigens. However, this residual low-avidity T-cell repertoire has antitumor activity. In this study, we compared the immune responses of Her-2/neu mice immunized with dendritic cells (DCs) pulsed with soluble neu protein or with apoptotic tumor cells. Analysis of the antitumor response shows that Her-2/neu mice vaccinated with DCs pulsed with Her-2/neu antigens retard tumor growth; however, vaccination with DCs pulsed with apoptotic tumor cells induces a stronger antitumor effect. Administration of multiple immunizations in combination with the costimulatory agonist anti-OX40 or anti-4-1BB MAb significantly enhanced the immune responses in these mice, resulting in complete tumor rejection if the tumor burden was small and substantial tumor reduction with a larger tumor burden. These results have important implications for the design of tumor vaccination strategies, suggesting that the use of vaccines that stimulate a broad immune response in combination with costimulatory molecules as immunomodulators could significantly improve the antitumor immune response in tolerant hosts. (C) 2005 Wiley-Liss, Inc.