The Immune Biology of Microsatellite-Unstable Cancer

abstract

Deficient DNA mismatch repair (MMR) boosts the accumulation of frameshift mutations in genes encompassing coding microsatellites (cMS). This results in the translation of proteins with mutation-induced frameshift peptides (neoantigens) rendering microsatellite-unstable (MSI) cancers highly immunogenic. MSI cancers express a defined set of neoantigens resulting from functionally relevant driver mutations, which are shared by most MSI cancers. Patients with MSI cancers and healthy individuals affected by Lynch syndrome, an inherited predisposition for MSI cancers, develop specific immune responses against these neoantigens. In this review, we summarize our current understanding of the immune biology of MSI cancers and outline new concepts and research directions to develop not only therapeutic treatments, but also preventive vaccines based on the MSI cancer genome landscapes.

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Trends

DNA MMR deficiency in MSI cancers triggers the generation of frameshift mutations.

Given that some of these mutations apparently act as driver mutations, they are shared by most MSI cancers.

These mutations give rise to highly immunogenic frameshift peptide (FSP) neoantigens, triggering immune responses in patients.

Recent studies have demonstrated that patients with MSI cancers benefit from immune checkpoint modulation.

Immune checkpoint modulation and potentially vaccination with MSI-specific FSP antigens are promising strategies for the treatment and prevention of MSI cancers.

Hereditary MSI cancers developing in Lynch syndrome are an ideal model to evaluate the feasibility of cancer-preventive vaccines in general.