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.