The immune biology of microsatellite unstable cancer

Abstract

Lynch syndrome-associated cancers arise through DNA mismatch repair (MMR) deficiency. MMR deficiency boosts the accumulation of insertion/deletion mutations at repetitive microsatellite sequences throughout the cancer cell genome (microsatellite instability, MSI). As microsatellite sequences are common in gene-encoding regions, MMR deficiency can cause gene inactivation through frameshift mutations. These frameshift mutations can trigger the generation of mutant proteins carrying novel amino acid sequences resulting from a shift of the translational reading frame (frameshift neoantigens). MSI cancers express a defined set of neoantigens, which are the direct result of functionally relevant driver mutations. The fact that these mutation events not only always affect the same genes but also exactly the same microsatellite loci within these genes leads to the unique situation that most MSI cancers share a precisely defined set of mutational neoantigens. MSI cancer patients frequently develop immune responses against these neoantigens. Surprisingly, such immune responses were also observed in tumor-free Lynch syndrome carriers, indicating that Lynch syndrome is characterized by lifelong interaction between the immune system and precancerous cells. We discuss the current knowledge about driver mutation-derived neoantigens, immune evasion mechanisms of MSI cancers, and potential clinical approaches to improve the host’s immune response against frameshift neoantigens.