Kim Jin H, Majumder Nilanjana, Lin Honghui, Chen Janet, Falo Louis D, You Zhaoyang
Department of Dermatology and University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Mol Ther. 2005 Jun;11(6):941-9. doi: 10.1016/j.ymthe.2005.01.003.
The rapid growth and ruthless metastasis of tumors demand effective broad immune responses. Dendritic cells (DCs) are critical in developing tumor vaccines. Recent investigations have been focused on modifying tumor antigens to target DCs to induce immune responses efficiently in vivo. In this study, human hsp70 was fused to the extracellular domain of rat Her2/Neu (NeuEDhsp70) for enhancing anti-tumor immunity in aggressive breast tumor models. NeuEDhsp70-conditioned DCs produced significant IL-12p40 and effectively presented NeuED antigens to T cells in vitro. NeuEDhsp70 DNA vaccine induced enhanced Neu-specific antibody and IFN-gamma-producing cellular immune responses in vivo. Although NeuEDhsp70 and NeuED DNA vaccines elicited comparable therapeutic anti-tumor immunity in an aggressive primary breast tumor model, NeuEDhsp70 DNA vaccine significantly increased survival and reduced metastasis in an aggressive spontaneous metastatic breast tumor model. Results from animal experiments with depletion of immune cells or with deficiency of CD40 molecules indicate that T cells and CD40 molecules are critical in the anti-tumor immunity induced by NeuEDhsp70 DNA vaccine. These observations suggest that NeuEDhsp70 DNA vaccine is a promising reagent to induce potent anti-tumor immunity to an aggressive spontaneous metastatic breast tumor.
肿瘤的快速生长和无情转移需要有效的广泛免疫反应。树突状细胞（DCs）在开发肿瘤疫苗方面至关重要。最近的研究集中在修饰肿瘤抗原以靶向DCs，从而在体内有效诱导免疫反应。在本研究中，将人热休克蛋白70（hsp70）与大鼠Her2/Neu的细胞外结构域融合（NeuEDhsp70），以增强侵袭性乳腺癌模型中的抗肿瘤免疫力。NeuEDhsp70处理的DCs在体外产生大量白细胞介素-12p40，并有效地将NeuED抗原呈递给T细胞。NeuEDhsp70 DNA疫苗在体内诱导增强的Neu特异性抗体和产生干扰素-γ的细胞免疫反应。尽管在侵袭性原发性乳腺癌模型中，NeuEDhsp70和NeuED DNA疫苗引发了相当的治疗性抗肿瘤免疫力，但在侵袭性自发性转移性乳腺癌模型中，NeuEDhsp70 DNA疫苗显著提高了生存率并减少了转移。免疫细胞耗竭或CD40分子缺陷的动物实验结果表明，T细胞和CD40分子在NeuEDhsp70 DNA疫苗诱导的抗肿瘤免疫中至关重要。这些观察结果表明，NeuEDhsp70 DNA疫苗是一种有前景的试剂，可诱导对侵袭性自发性转移性乳腺癌产生强大的抗肿瘤免疫力。
