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Microsatellite instable (MSI) cancers express frameshift-mutated antigens, the C-terminal polypeptides of which are foreign to the immune system. Consequently, these antigens constitute a unique pool of tumor-specific antigens that can be exploited for patient diagnosis and selective, immune-mediated targeting of cancers. However, other than their sequence, very little is known about the characteristics of the majority of these proteins. We therefore developed a methodology for predicting their immunogenic behavior that is based on a gene-expression system, in which each of the proteins was fused to a short C-terminal polypeptide comprising two epitopes that can be readily detected by T-cells and antibodies, respectively. In this manner, accumulation of the antigens and processing of peptides derived thereof into MHC can be monitored systematically. The antigens, which accumulate in the cells in which they are synthesized, are of primary interest for cancer immunotherapy, because peptide epitopes derived thereof can be presented by dendritic cells in addition to the tumor cells themselves. As a result, these antigens constitute the best targets for a coordinated immune response by both CD8+ and CD4+ T-cells, which increases the likelihood that tumor-induced immunity would be detectable against these antigens in cancer patients, as well as the potential value of these antigens as components of anticancer vaccines. Our data indicate that, of 15 frameshift-mutated antigens examined in our study, 4 (TGFβR2-1, MARCKS-1, MARCKS-2 and CDX2-2) are of primary interest, and 4 additional antigens (TAF1B-1, PCNXL2-2, TCF7L2-2 and Baxα+1) are of moderate interest for further tumor immunological research. © 2008 Wiley-Liss, Inc.