Abstract
The immune system can recognize and attack cancer cells, especially those with a high load of mutation-induced neoantigens. Such neoantigens are particularly abundant in DNA mismatch repair (MMR)-deficient, microsatellite-unstable (MSI) cancers. MMR deficiency leads to insertion/deletion (indel) mutations at coding microsatellites (cMS) and to neoantigen-inducing translational frameshifts. The abundance of mutational neoantigens renders MSI cancers sensitive to immune checkpoint blockade. However, the neoantigen landscape of MMR-deficient cancers has not yet been systematically mapped. In the present study, we used a novel tool to monitor neoantigen-inducing indel mutations in MSI colorectal and endometrial cancer. Our results show that MSI cancers share several highly immunogenic neoantigens that result from specific, recurrent indel mutation events. Notably, the frequency of such indel mutations was negatively correlated to the predicted immunogenicity of the resulting neoantigens. These observations suggest continuous immunoediting of emerging MMR-deficient cells during tumor evolution.
One sentence summary Quantitative indel mutation analysis reveals evidence of immune selection in mismatch repair-deficient cancers
Footnotes
↵$ shared first authorship
Glossary
- ELS
- Epitope likelihood score
- GELS
- General epitope likelihood score
- IRS
- Immune relevance score, based on the mutation frequency (ReFrame) and the GELS
- M1
- Reading frame resulting from the deletion of one nucleotide or insertions of two nucleotides
- M2
- Reading frame resulting from the deletions of two nucleotides or insertion of one nucleotide
- m1, m2, m3, etc.
- Minus one, two, three base pair deletions
- p1, p2, p3, etc.
- Plus one, two, three base pair insertions
- ReFrame
- REgression-based FRAMEshift quantification
