p53-based immunotherapy of cancer
p53-based immunotherapy of cancer
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DOI：
10.1615/critrevimmunol.v18.i1-2.40
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发表时间：
1998-01-01
影响因子：
1.3
通讯作者：
DeLeo, AB
中科院分区：
文献类型：
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作者：
DeLeo, AB
靶向p53错义突变的免疫治疗，发生在近一半的人类肿瘤中，受到几个因素的限制，包括抗原加工和呈递的限制。由于突变的p53分子在表达p53突变的肿瘤中的积累，一种替代方法将是靶向野生型序列、CTL定义的p53表位。显然，自身免疫反应的可能性是这种疗法的主要潜在缺点。用骨髓来源的树突状细胞（DC）免疫BALB/c小鼠，所述树突状细胞（DC）在GM-CSF/IL-4的存在下产生并且用H-2K（d）结合野生型p53（232-240）肽预脉冲，已经显示诱导抗肽CTL。这些效应子对p53（232-240）表位外表达p53错义突变的肉瘤具有交叉反应性，而对p53表位内表达p53错义突变的肉瘤不具有交叉反应性。在免疫和治疗模型中，p53肽脉冲的基于DC的疫苗显示在诱导肿瘤排斥方面是有效的，而对幼稚小鼠没有任何可观察到的有害作用。鼠模型现在已经扩展到包括使用基因修饰的DC为基础的疫苗。
Immunotherapy targeting p53 missense mutations, which occur in nearly half of all human tumors, is limited by several factors, including the constraints of antigen processing and presentation. Due to the accumulation of mutated p53 molecules in tumors expressing p53 mutations, an alternative approach would be to target wild-type sequence, CTL-defined p53 epitopes. Obviously, the possibility of an autoimmune response is a major potential drawback to this therapy. Immunization of BALB/c mice with bone marrow-derived dendritic cells (DC) generated in the presence of GM-CSF/IL-4 and prepulsed with the H-2K(d)-binding wild-type p53(232-240) peptide has been shown to induce anti-peptide CTL. These effecters were cross-reactive against sarcomas expressing p53 missense mutations outside of the p53(232-240) epitope, but not within it. Mitogen-activated splenocytes, which express elevated levels of p53, were not sensitive to these CTL. The p53 peptide-pulsed DC-based vaccine was shown to be effective in inducing tumor rejection in immunization and therapy models in the absence of any observable deleterious effect on naive mice. The murine model has now been extended to include the use of genetically modified DC-based vaccines as well.