Abstract
BackgroundNeoantigens 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.MethodsWe 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.ResultsThe 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.ConclusionsThese 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.
Highlights
Neoantigens that arise as a consequence of tumor-specific mutations can be recognized by T lymphocytes leading to effective immune surveillance
The cell line with the highest number of variants (SNU1040) carried inactivating alterations in both MLH1 and POLE (Additional file 1: Figure S1b). These results are consistent with what has been reported in colorectal cancer (CRC) patients carrying alterations in the mismatch repair (MMR) DNA repair pathway, indicating that the cell models included in this study broadly recapitulate what is observed in clinical specimens [27]
We sought to minimize confounding effects due to differences in cell-intrinsic doubling times (Table 1); we calculated the doubling time of all cell models (Table 1, Additional file 1: Figure S4)
Summary
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. We exploited CRC as a model system to understand how alterations in DNA repair pathways modulate neoantigen profiles over time. Anticancer therapies based on immune-checkpoint blockade are often remarkably effective but benefit only a minor fraction of cancer patients [1]. Rospo et al Genome Medicine (2019) 11:42 we exploit CRCs as a model system to understand whether mutational burden and neoantigen profile of human tumors evolve over time as a result of their distinctive genomic landscapes.
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