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Unformatted text preview: Immune evasion of microsatellite unstable colorectal cancers Matthias Kloor 1,2 , Sara Michel 1,2 and Magnus von Knebel Doeberitz 1,2 1 Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Molecular Medicine Partnership Unit (MMPU), Heidelberg, Germany 2 Group Cancer Early Detection, German Cancer Research Center (DKFZ), Heidelberg, Germany Colorectal cancers (CRC) develop through 2 major pathways of genetic instability. In contrast to the majority of CRCs, which are characterized by chromosomal instability, high-level microsatellite unstable (MSI-H) CRCs arise as a consequence of the loss of DNA mismatch repair (MMR) functions and show accumulation of insertion and deletion mutations particularly in microsatellite sequences. MSI-H occurs in about 15% of CRCs, and virtually all CRCs occurring in the context of the hereditary cancer-predisposing Lynch syndrome. These tumors are characterized by a comparably good prognosis and a low frequency of distant metastases. Because of the expression of a defined set of tumor-specific antigens, MSI-H CRCs elicit a strong local and systemic antitumoral immune response of the host and therefore use different strategies to evade the control of the immune system. In this review, we will summarize novel molecular mechanisms that at the same time drive pathogenesis, immunogenicity and immune evasion during the development and progression of MSI-H CRCs. We will focus on the current knowledge about alterations in human leukocyte antigen (HLA) antigen presentation and discuss how immune evasion—while offering protection against local antitumoral immune responses—paradoxically might interfere with the ability of the tumor to form distant organ metastases. What Is Microsatellite Instability? Colorectal cancer (CRC) is a pathogenetically heterogeneous disease. Although the majority of CRCs shows chromosomal instability, about 15% of CRCs occur because of defects in the DNA mismatch repair (MMR) system. 1–3 MMR-deficient CRC may develop sporadically or in the context of the hered- itary nonpolyposis colorectal cancer (HNPCC) or Lynch syn- drome. 4,5 DNA MMR deficiency induces a high number of mutational events mainly consisting of insertion and deletion mutations at microsatellites, because these structures are par- ticularly prone to DNA polymerase slippage during DNA replication. 6 The resulting phenotype is termed high-level microsatellite instability (MSI-H). MSI-H CRCs are characterized by a distinct pathology that is closely connected to the occurrence of mutations affecting microsatellites in gene-encoding regions (coding microsatellites, cMS). Although mutations affecting microsa- tellites in intergenic or noncoding regions are mostly of unknown functional significance, insertions or deletions of nucleotides in cMS can result in defined translational frame- shifts that can interfere with protein function 7,8 (Fig. 1)....
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This document was uploaded on 08/24/2011.
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