Exploring Mistranslation as a Source of Neoantigens in Cancer Immunotherapy

The importance of neoantigens in cancer immunotherapies has been underscored by recent successes in clinical trials. However, these breakthroughs mostly rely on tumor-specific somatic mutations, which represent only a small portion of cancers. A broader and promising source of neoantigens may come from mistranslation events in cancer cells, offering the potential to target a wider range of cancers.

To test this idea, a team of scientists developed a comprehensive proteogenomics workflow that integrates immunopeptidomics, genomics, and functional assays to highlight the value of these alternative neoantigens. Using tRNA wybutosine (yW)-synthesizing protein 2 (TYW2) as a model, they created a cancer cell line with a TYW2 gene knockout, then generated multi-omics data from both the knockout and control cell lines to compare differences.

For confident immunopeptide discovery, they built a pipeline combining database search with PEAKS de novo sequencing, allowing detection of both canonical and non-canonical peptides. Their findings revealed that TYW2 loss results in immunogenic out-of-frame peptides. More importantly, this loss was also correlated with clinical outcomes, suggesting strong therapeutic potential for these peptides.

To verify the quality of the immunopeptidomics results, the authors compared attributes of canonical and non-canonical peptides (identified through PEAKS de novo) such as peptide length distribution, hydrophobicity index, retention time (RT) shifts between predicted and measured values, and spectral similarity. Across these metrics, non-canonical peptides showed similar patterns to canonical ones, confirming the high confidence of PEAKS de novo identifications.

Tip:
In the PEAKS DeepNovo peptidome workflow, many of these quality metrics are available in either plots or tables. You can easily access them in the result or QC pages.

📄 Read the full article here:
Cell – Cancer Cell