Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Clinical Cancer Genetics Program, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Mol Aspects Med. 2023 Oct;93:101204. doi: 10.1016/j.mam.2023.101204. Epub 2023 Jul 19.
Lynch Syndrome (LS) is one of the most common hereditary cancer syndromes, and is caused by mutations in one of the four DNA mismatch repair (MMR) genes, namely MLH1, MSH2, MSH6 and PMS2. Tumors developed by LS carriers display high levels of microsatellite instability, which leads to the accumulation of large numbers of mutations, among which frameshift insertion/deletions (indels) within microsatellite (MS) loci are the most common. As a result, MMR-deficient (MMRd) cells generate increased rates of tumor-specific neoantigens (neoAgs) that can be recognized by the immune system to activate cancer cell killing. In this context, LS is an ideal disease to leverage immune-interception strategies. Therefore, the identification of these neoAgs is an ongoing effort for the development of LS cancer preventive vaccines. In this review, we summarize the computational methods used for in silico neoAg prediction, including their challenges, and the experimental techniques used for in vitro validation of their immunogenicity. In addition, we outline results from past and on-going vaccine clinical trials and highlight avenues for improvement and future directions.
林奇综合征（LS）是最常见的遗传性癌症综合征之一，由四个 DNA 错配修复（MMR）基因之一的突变引起，即 MLH1、MSH2、MSH6 和 PMS2。LS 携带者发展的肿瘤显示出高水平的微卫星不稳定性，导致大量突变的积累，其中微卫星（MS）位点内的移码插入/缺失（indels）是最常见的。结果，MMR 缺陷（MMRd）细胞产生增加的肿瘤特异性新抗原（neoAgs）的速率，这些新抗原可以被免疫系统识别以激活癌细胞杀伤。在这种情况下，LS 是利用免疫干预策略的理想疾病。因此，鉴定这些 neoAgs 是开发 LS 癌症预防性疫苗的一项持续努力。在这篇综述中，我们总结了用于计算机 neoAg 预测的计算方法，包括它们的挑战，以及用于体外验证其免疫原性的实验技术。此外，我们概述了过去和正在进行的疫苗临床试验的结果，并强调了改进和未来方向的途径。
