BACKGROUND Neoantigens that arise as a consequence of tumor-specific mutations can be recognized by T lymphocytes leading to effective immune surveillance. In colorectal cancer (CRC) and other tumor types, a high number of neoantigens is associated with patient response to immune therapies. The molecular processes governing the generation of neoantigens and their turnover in cancer cells are poorly understood. We exploited CRC as a model system to understand how alterations in DNA repair pathways modulate neoantigen profiles over time. METHODS We performed whole exome sequencing (WES) and RNA sequencing (RNAseq) in CRC cell lines, in vitro and in vivo, and in CRC patient-derived xenografts (PDXs) to track longitudinally genomic profiles, clonal evolution, mutational signatures, and predicted neoantigens. RESULTS The majority of CRC models showed remarkably stable mutational and neoantigen profiles; however, those carrying defects in DNA repair genes continuously diversified. Rapidly evolving and evolutionary stable CRCs displayed characteristic genomic signatures and transcriptional profiles. Downregulation of molecules implicated in antigen presentation occurred selectively in highly mutated and rapidly evolving CRC. CONCLUSIONS These results indicate that CRCs carrying alterations in DNA repair pathways display dynamic neoantigen patterns that fluctuate over time. We define CRC subsets characterized by slow and fast evolvability and link this phenotype to downregulation of antigen-presenting cellular mechanisms. Longitudinal monitoring of the neoantigen landscape could be relevant in the context of precision medicine.

中文翻译：

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具有DNA修复缺陷的大肠癌中不断发展的新抗原谱。

背景技术由于肿瘤特异性突变而产生的新抗原可以被T淋巴细胞识别，从而导致有效的免疫监视。在结直肠癌（CRC）和其他肿瘤类型中，大量新抗原与患者对免疫疗法的反应有关。对新抗原的产生及其在癌细胞中的转换的分子过程知之甚少。我们利用CRC作为模型系统来了解DNA修复途径的变化如何随时间调节新抗原谱。方法我们在CRC细胞系中进行了全外显子组测序（WES）和RNA测序（RNAseq），在体内和体外以及在CRC患者衍生的异种移植物中（PDXs）追踪纵向基因组图谱，克隆进化，突变特征和预测新抗原。结果多数CRC模型显示出非常稳定的突变和新抗原谱。然而，那些携带DNA修复基因缺陷的人不断多样化。快速进化和进化稳定的CRCs显示出特征性的基因组特征和转录特征。涉及抗原呈递的分子的下调选择性地发生在高度突变和快速发展的CRC中。结论这些结果表明，在DNA修复途径中携带CRC的CRCs表现出动态的新抗原模式，该模式随时间波动。我们定义了以慢速和快速进化为特征的CRC亚群，并将该表型与抗原呈递细胞机制的下调联系起来。在精密医学的背景下，对新抗原景观的纵向监测可能是相关的。