Exploiting the Mutanome for Tumor Vaccination

作者：John C. Castle, Sebastian Kreiter, Jan Diekmann, Martin Löwer, Niels van de Roemer, Jos de Graaf, Abderraouf Selmi, Mustafa Diken, Sebastian Boegel, Claudia Paret, Michael Koslowski, Andreas N. Kuhn, Cedrik Michael Britten, Christoph Huber, Özlem Türeci, Uğur Şahin · 发表于：Cancer Research · 年份：2012 · DOI：10.1158/0008-5472.can-11-3722 · 被引用次数：831 · 研究领域：vaccines and immunoinformatics approaches、Immunotherapy and Immune Responses、Monoclonal and Polyclonal Antibodies Research

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, the...