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Molecular Medicine Partnership Unit

 

Research Focus 1: Identification and utilization of novel target genes

 

Pathogenetic mechanisms of MSI tumors 

Microsatellite unstable (MSI) tumors exhibit a variety of histoclinicopathological features including mucinous histology and improved prognosis when compared to their microsatellite stable (MSS) counterparts. Biallelic mutational inactivation of some MSI target genes is frequently observed and is generally believed to drive MSI tumorigenesis. Focussing on the pathogenetic mechanisms of these MSI tumors we recently uncovered novel immune evasion mechanisms characteristic of MSI cancers.

We identified novel precursor lesions of MSI colorectal cancers in Lynch syndrome, the most common inherited cancer predisposition syndrome. This discovery has helped to establish a new model of MSI tumor formation. In addition, we discovered potential correlations between functional inactivation of specific MSI target genes and cell surface glycosylation patterns.

Development of a novel frameshift peptide neoantigen vaccine in MSI tumor patients 

MMR deficiency-induced mutations of coding microsatellite sequences are drivers of MSI cancer development. Expression of specific mutated genes leads to the synthesis of truncated proteins with C-terminal frameshift neoantigens. Exactly the same neoantigens occur in the majority of MSI cancers, and they can be presented to the immune system by MHC antigens. Therefore, genes with coding microsatellites with high mutation frequency represent ideal targets for immunological response.

Our MMPU group has pioneered research on the immune biology of MSI cancers for many years. In immunological studies we identified several frameshift derived immunogenic peptides and subsequently showed that MSI tumor cells can be lysed in vitro by cytotoxic T-cells in a peptide specific manner. A Phase I/II study has been successfully completed, demonstrating that vaccination with MSI-specific frameshift peptide neoantigens in patients with MSI colorectal cancer of stage III and IV consistently induces specific T cell-based and humoral immune responses.

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