Microsatellite Instability in Colorectal Cancers: Carcinogenesis, Neo-Antigens, Immuno-Resistance and Emerging Therapies

Abstract

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.

Keywords: colorectal cancer; deficient mismatch repair; immune checkpoint inhibitor; immunotherapy; microbiota; microsatellite instability.

Figure 1

Mismatch repair mechanism. The MutSα (MSH2-MSH6 dimer) recognizes single-base-pair mismatch then surrounds the DNA like a clamp and the MutLα complex (MLH1-PMS2 dimer) is fixed on. The complex MutSβ (MSH2-MSH3 dimer) recognizes insertion–deletion loops, then the MutLα complex is fixed on. Different enzymes (Exonuclease, PCNA, and DNA polymerase) then intervene to excise the mismatched base and to synthesize a new strand of DNA. PCNA: Proliferating cell nuclear antigen. ADP: Adenosine diphosphate. ATP: Adenosine triphosphate.

Figure 2

Mismatch Repair deficiency: Consequences on tumor biology and outcome in colorectal cancer. The upper right part of the figure shows an example of frameshift mutation in the tumor growth factor β receptor II (TGFβ-RII) gene. The single nucleotide deletion of an adenosine (A) is not corrected by a deficient mismatch repair, leading to a frameshift mutation and a modified sequence of amino-acids corresponding to the frameshift peptide (FSP02). The left part of the figure summarizes the consequence of frameshift mutation on tumor progression. The lower part of the figure summarizes consequences of such uncorrected mutations on immune tumor environment and their clinical impact. M0: Non metastatic colorectal cancer; M+: Metastatic colorectal cancer.

Figure 3

pMMR/MSS colorectal cancers and dMMR/MSI colorectal cancers have different microbiota.