The sharedneoantigen landscape of MSI cancers reflects immunoediting during tumor evolution

The immune system can recognize and attack cancer cells, especially those with a high load of mutation-induced neo antigens. Such neo antigens 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 neo antigen-inducing translational frameshifts. The abundance of mutational neo antigens 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 neo antigen-inducing indel mutations in MSI colorectal and endometrial cancer. Our results show that MSI cancers share several highly immunogenic neo antigens 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 neo antigens. 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