The sharedneoantigen landscape of MSI cancers reflects immunoediting during tumor evolution

Abstract

AbstractThe immune system can recognize and attack cancer cells, especially those with a high load of mutation-inducedneoantigens. Suchneoantigens 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 toneoantigen-inducing translational frameshifts. The abundance of mutationalneoantigens 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 monitorneoantigen-inducing indel mutations in MSI colorectal and endometrial cancer. Our results show that MSI cancers share several highly immunogenicneoantigens that result from specific, recurrent indel mutation events. Notably, the frequency of such indel mutations was negatively correlated to the predicted immunogenicity of the resultingneoantigens. These observations suggest continuous immunoediting of emerging MMR-deficient cells during tumor evolution.One sentence summaryQuantitative indel mutation analysis reveals evidence of immune selection in mismatch repair-deficient cancers