Exploiting the Mutanome for Tumor Vaccination
Exploiting the Mutanome for Tumor Vaccination
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DOI：
10.1158/0008-5472.can-11-3722
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发表时间：
2012-03-01
期刊：
影响因子：
11.2
通讯作者：
Sahin, Ugur
中科院分区：
文献类型：
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作者：
Castle, John C.;Kreiter, Sebastian;Sahin, Ugur
多个基因事件和随后的克隆进化推动了癌症的发生，使单一靶向药物难以消除疾病。因此，克隆异质性产生的基因突变的多样性代表了多表位肿瘤疫苗接种的理想环境。在这里，我们使用下一代测序外显子组重测序来鉴定B16F10小鼠黑色素瘤细胞中的962个非同义体细胞点突变，其中563个突变存在于表达基因中。潜在的驱动突变发生在经典的肿瘤抑制基因和控制细胞增殖、黏附、迁移和凋亡的原癌信号通路中。已知在人类黑色素瘤中发生改变的Aim1和Trrap突变包括在这些发现中。用编码突变表位的长肽免疫小鼠，确定50个有效突变的免疫原性和特异性。这些多肽中有三分之一被发现是免疫原性的，与野生型序列相比，这一组中60%的多肽优先针对突变序列激发免疫反应。在肿瘤移植模型中，多肽免疫可以在体内保护和治疗环境中控制肿瘤，从而使包括单一氨基酸替换的突变表位成为有效的疫苗。总之，我们的发现提供了B16F10黑色素瘤突变组的全面图景，该突变组被广泛用于免疫治疗研究。此外，它们还提供了对非同义碱基替换突变的免疫原性程度的洞察。最后，他们认为，使用深度测序来系统分析免疫原性突变可能为癌症患者的个性化免疫治疗铺平道路。癌症资源；72(5)；1081-91。(C)2012年AACR。
Multiple genetic events and subsequent clonal evolution drive carcinogenesis, making disease elimination with single-targeted drugs difficult. The multiplicity of gene mutations derived from clonal heterogeneity therefore represents an ideal setting for multiepitope tumor vaccination. Here, we used next generation sequencing exome resequencing to identify 962 nonsynonymous somatic point mutations in B16F10 murine melanoma cells, with 563 of those mutations in expressed genes. Potential driver mutations occurred in classical tumor suppressor genes and genes involved in proto-oncogenic signaling pathways that control cell proliferation, adhesion, migration, and apoptosis. Aim1 and Trrap mutations known to be altered in human melanoma were included among those found. The immunogenicity and specificity of 50 validated mutations was determined by immunizing mice with long peptides encoding the mutated epitopes. One-third of these peptides were found to be immunogenic, with 60% in this group eliciting immune responses directed preferentially against the mutated sequence as compared with the wild-type sequence. In tumor transplant models, peptide immunization conferred in vivo tumor control in protective and therapeutic settings, thereby qualifying mutated epitopes that include single amino acid substitutions as effective vaccines. Together, our findings provide a comprehensive picture of the mutanome of B16F10 melanoma which is used widely in immunotherapy studies. In addition, they offer insight into the extent of the immunogenicity of nonsynonymous base substitution mutations. Lastly, they argue that the use of deep sequencing to systematically analyze immunogenicity mutations may pave the way for individualized immunotherapy of cancer patients. Cancer Res; 72(5); 1081-91. (C) 2012 AACR.