PT - JOURNAL ARTICLE AU - Alexej Ballhausen AU - Moritz Jakob Przybilla AU - Michael Jendrusch AU - Saskia Haupt AU - Elisabeth Pfaffendorf AU - Markus Draxlbauer AU - Florian Seidler AU - Sonja Krausert AU - Aysel Ahadova AU - Martin Simon Kalteis AU - Daniel Heid AU - Johannes Gebert AU - Maria Bonsack AU - Sarah Schott AU - Hendrik Bläker AU - Toni Seppälä AU - Jukka-Pekka Mecklin AU - Sanne Ten Broeke AU - Maartje Nielsen AU - Vincent Heuveline AU - Julia Krzykalla AU - Axel Benner AU - Angelika Beate Riemer AU - Magnus von Knebel Doeberitz AU - Matthias Kloor TI - The shared <em>neo</em>antigen landscape of MSI cancers reflects immunoediting during tumor evolution AID - 10.1101/691469 DP - 2019 Jan 01 TA - bioRxiv PG - 691469 4099 - http://biorxiv.org/content/early/2019/07/16/691469.short 4100 - http://biorxiv.org/content/early/2019/07/16/691469.full AB - 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 cancersELSEpitope likelihood scoreGELSGeneral epitope likelihood scoreIRSImmune relevance score, based on the mutation frequency (ReFrame) and the GELSM1Reading frame resulting from the deletion of one nucleotide or insertions of two nucleotidesM2Reading frame resulting from the deletions of two nucleotides or insertion of one nucleotidem1, m2, m3, etc.Minus one, two, three base pair deletionsp1, p2, p3, etc.Plus one, two, three base pair insertionsReFrameREgression-based FRAMEshift quantification