Molecular Pathogenesis and Immune Biology of Intestinal MSI Tumors in a DNA Mismatch Repair-Deficient Mouse Model
Final Report Abstract
This research project sought to explore the molecular and immunological features of MSI tumors in Lynch Syndrome (LS) VCMsh2 mice by identifying recurrent coding mononucleotide frameshift mutations (FSMs) and derived immunogenic frameshift peptides (FSPs) shared by many mouse MSI intestinal tumors. Evaluating the immunogenicity of such shared neoantigens for vaccination is essential for developing novel preclinical immunoprevention and/or chemo/immunoprevention approaches. Therefore we performed (1) Histopathological analysis of VcMsh2loxP mouse intestines (2) Bioinformatic identification of all cMNRs in the mouse genome (3) Mutation profiling/Identification of recurrent cMNR mutations in MSI intestinal tumors (4) Immune cell infiltration, FSP immunogenicity and (even more than expected) FSP vaccine testing. New findings: A. Novel databases of all mouse cMNRs, mouse-human conserved cMNRs and pathway-specific mouse-human conserved cMNRs. B. First time evidence for MMR-deficient crypts in mouse intestinal mucosa. C. Early occurrence and age-dependent increase of cMNR frameshift mutations (FSM) in MSI intestinal tumors of LS mice. D. First evidence for FSMs in mouse-human conserved cMNRs of CRC-relevant pathways (Wnt, Notch, Tgfb). E. Identification of four immunogenic FSP neoantigens for vaccination that induced CD4/CD8 T cell response in naïve C57BL/6 mice. F. Preclinical evidence for reduced gastrointestinal tumor burden and prolonged overall survival in LS mice by quatro-valent FSP vaccine Although recurrent FSMs in several genes have been found in MSI intestinal tumors of LS mice and postively selected MSI target genes can be predicted, their growth promoting effects need to be demonstrated by functional experiments. Moreover, sample sizes of tumors and candidate cMNRs need to be increased for refined regression analysis. Likewise, more FSM-derived immunogenic FSPs and vaccine-associated FSP mixtures as well as different boosting regimens, adjuvant choices and combinations with chemotherapeutic treatments need to be tested. Recurrent FSMs and shared FSP neoantigens in mouse MSI tumors allow development of novel chemo/immunoprevention strategies.
Publications
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Recurrent Frameshift Neoantigen Vaccine Elicits Protective Immunity With Reduced Tumor Burden and Improved Overall Survival in a Lynch Syndrome Mouse Model. Gastroenterology, Vol. 161. 2021, Issue 4, pp. 1288-1302.e13.
Johannes Gebert, Ozkan Gelincik, Mine Oezcan-Wahlbrink, Jason D.Marshall, Alejandro Hernandez-Sanchez, Katharina Urban, Mark Long, Eduardo Cortes, ElenaTosti, Peer Bork et al.
