<> "The repository administrator has not yet configured an RDF license."^^ . <> . . "Models for Immune Response and Immune Evasion in MSI Cancer and Lynch Syndrome"^^ . "Microsatellite-unstable (MSI) cancers occurring in the context of the hereditary Lynch\r\nsyndrome or as sporadic cancers elicit pronounced tumor-specific immune responses.\r\nThe pronounced immune response was shown to be closely associated with frameshift\r\npeptides (FSP) that are generated as a result of deficiency in DNA mismatch repair\r\nsystem leading to insertion/deletion mutations in coding microsatellites (cMS). FSP\r\nneoantigens are long antigenic amino acid stretches that bear multiple epitopes to be\r\npresented. There is no central tolerance against FSPs, and shared FSPs derived from\r\ndriver mutations are promising candidates for vaccination approaches to treat or\r\nprevent MSI cancers. In the present thesis, the main goals were to set up a mouse model\r\nfor the immunology of MSI cancers and to systematically identify immune evasion\r\nmechanisms in MSI cancers.\r\nA murine model is essential to characterize alterations of immune responses over time,\r\nin all stages of cancer and pre-cancerous stages. In addition, it allows testing an FSP\r\nvaccine for efficacy in tumor prevention and treatment, either as a single agent or on\r\ncombination with other immune-modulatory drugs. To establish such a model, the\r\ncomplete mouse genome was screened and genes bearing cMS were detected. After\r\nmutation and expression analysis by using murine Lynch tumors, epitopes of the most\r\npromising potential FSP candidates were predicted by using the Syfpeithi and netMHC\r\nalgorithms. Immunogenicity of the 10 FSPs with the highest ranks was analyzed by\r\nvaccinating C57BL/6 mice and analyzing immune responses using IFNg ELISpot. Four\r\nFSPs were identified that were highly immunogenic and inducing spot numbers higher\r\nthan Ova control peptides: Maz (-1) and Senp6 (-1) induced only CD4 T cell responses,\r\nXirp1 (-1) induced only CD8 T cell and Nacad (-1) induced both CD4 and CD8 T cell\r\nresponses. Peptide-specific IgG Elisa demonstrated that three of the peptides Senp6 (-1),\r\nMaz (-1) and Nacad (-1) also induced humoral immune response. Immunogenic regions\r\nof the peptides could be mapped to the C-terminus of Senp6 (-1) and Xirp (-1) and to the\r\nN-terminus of Nacad (-1), whereas the antigenic region for Maz (-1) spanned almost the\r\nentire peptide. These results suggest that the Lynch mouse model is well suitable for\r\nevaluating the efficacy of FSP vaccination to treat and even prevent tumors in Lynch\r\nsyndrome.\r\nII\r\nThe second aim of this thesis was to systematically analyze immune evasion\r\nmechanisms in MSI cancer. We first analyzed mutations of genes related to MHC class I\r\nantigen presentation in publicly accessible mutation databases. The mutation data of 91\r\nMSI patients in the DFCI cohort showed that 72% of all MSI CRC tumors had defects in\r\nMHC class I presentation; displayed by at least one mutation in the corresponding genes\r\n(B2M, TAP1, TAP2, HLA-A, HLA-B, HLA-C and NLRC5). Mutual exclusivity analysis\r\nrevealed that mutations affecting B2M were negatively related to HLA-B mutations,\r\nwhereas there was a strong positive correlation between HLA class I heavy chain\r\nmutations. These results indicate that there is a strong immunoselection in MSI\r\ntumorigenesis, leading to immune evasion through mutations of MHC class I-related\r\ngenes in more than two-thirds of MSI cancers. We identified NLRC5 mutations as a\r\npotential novel immune evasion mechanism in the database analysis; therefore,\r\npotential consequences of NLRC5 inactivation were further analyzed in MSI colorectal\r\ncancer samples. We detected cMS mutations of NLRC5 in 4 out of 95 tumor samples\r\n(4.2%), three of them being one-basepair deletions and one silent mutation.\r\nImportantly, we detected low levels of MHC class I antigen expression in NLRC5-\r\nmutated tumors. One tumor showed partial reduction of MHC class I expression, which\r\ncolocalized with the NLRC5 mutation. These results suggest NLRC5 mutations as a novel\r\npotential mechanism of immune evasion in MSI cancer.\r\nTaken together, the present thesis led to the establishment of the first model to evaluate\r\nthe immune biology of MSI cancers and Lynch syndrome in the murine system.\r\nMoreover, it has established a comprehensive overview of immune evasion in MSI\r\ncancers, thus contributing to the development of better treatment strategies and\r\npotentially to the first cancer-preventive vaccine for non-viral human cancers."^^ . "2017" . . . . . . . "Mine"^^ . "Özcan"^^ . "Mine Özcan"^^ . . . . . . "Models for Immune Response and Immune Evasion in MSI Cancer and Lynch Syndrome (PDF)"^^ . . . "Thesis Mine Oezcan 171108.pdf"^^ . . . "Models for Immune Response and Immune Evasion in MSI Cancer and Lynch Syndrome (Other)"^^ . . . . . . "indexcodes.txt"^^ . . . "Models for Immune Response and Immune Evasion in MSI Cancer and Lynch Syndrome (Other)"^^ . . . . . . "lightbox.jpg"^^ . . . "Models for Immune Response and Immune Evasion in MSI Cancer and Lynch Syndrome (Other)"^^ . . . . . . "preview.jpg"^^ . . . "Models for Immune Response and Immune Evasion in MSI Cancer and Lynch Syndrome (Other)"^^ . . . . . . "medium.jpg"^^ . . . "Models for Immune Response and Immune Evasion in MSI Cancer and Lynch Syndrome (Other)"^^ . . . . . . "small.jpg"^^ . . "HTML Summary of #23709 \n\nModels for Immune Response and Immune Evasion in MSI Cancer and Lynch Syndrome\n\n" . "text/html" . . . "500 Naturwissenschaften und Mathematik"@de . "500 Natural sciences and mathematics"@en . .