Abstract
Simple SummaryA deficient mismatch repair system (dMMR) results in microsatellite instability (MSI). The MSI status of a tumor predicts the response to immune checkpoint inhibitors (ICI) that are now approved in patients with dMMR/MSI metastatic colorectal cancers. In addition to the mechanisms through which MSI can activate the immune system via particular neo-antigens, this review reports the clinical and pre-clinical strategies being developed in the case of resistance to ICI, including emerging therapies and new biomarkers.A defect in the DNA repair system through a deficient mismatch repair system (dMMR) leads to microsatellite instability (MSI). Microsatellites are located in both coding and non-coding sequences and dMMR/MSI tumors are associated with a high mutation burden. Some of these mutations occur in coding sequences and lead to the production of neo-antigens able to trigger an anti-tumoral immune response. This explains why non-metastatic MSI tumors are associated with high immune infiltrates and good prognosis. Metastatic MSI tumors result from tumor escape to the immune system and are associated with poor prognosis and chemoresistance. Consequently, immune checkpoint inhibitors (ICI) are highly effective and have recently been approved in dMMR/MSI metastatic colorectal cancers (mCRC). Nevertheless, some patients with dMMR/MSI mCRC have primary or secondary resistance to ICI. This review details carcinogenesis and the mechanisms through which MSI can activate the immune system. After which, we discuss mechanistic hypotheses in an attempt to explain primary and secondary resistances to ICI and emerging strategies being developed to overcome this phenomenon by targeting other immune checkpoints or through vaccination and modification of microbiota.
Highlights
The therapeutic impact of a deficient mismatch repair system leading to microsatellite instability (MSI) in colorectal cancers (CRCs) illustrates the importance of deciphering carcinogenesis at both the cellular and the molecular stages
The proficient mismatch repair system, which maintains microsatellite stability (MSS), is defined by the presence of functional proteins involved in this deoxyribonucleic acid (DNA) repair machinery: MutS protein homologue 2 (MSH2), MutS protein homologue 3 (MSH3), MutS protein homologue 6 (MSH6), Human mutL protein homologue 1 (MLH1), post-meiotic segregation increased homologue 1 (PMS1), and PMS1 homologue
Due to a high burden of neo-antigens derived from frameshift mutations, an immune response is efficient in most deficient mismatch repair system (dMMR)/MSI CRCs conferring a good prognosis of these tumors at an early stage of the disease
Summary
The therapeutic impact of a deficient mismatch repair system (dMMR) leading to microsatellite instability (MSI) in colorectal cancers (CRCs) illustrates the importance of deciphering carcinogenesis at both the cellular and the molecular stages. The proficient mismatch repair system (pMMR), which maintains microsatellite stability (MSS), is defined by the presence of functional proteins involved in this deoxyribonucleic acid (DNA) repair machinery: MutS protein homologue 2 (MSH2), MutS protein homologue 3 (MSH3), MutS protein homologue 6 (MSH6), Human mutL protein homologue 1. Cancers 2021, 13, 3063 homologue 2 (PMS2) These proteins work in dimers, MSH2 with MSH6 or MSH3 and MLH1. MutLα interacts the MutS via MLH1, and this coordination downstream events. The proliferating nuclearcellular antigen isthe essential for the of coordination ofrepair downstream repair events. Nuclear antigen (PCNA) is involved in MMR initiation as it interacts with MutSα Itand activates. PolymeraseIδ,[3,5]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
