Microsatellite instability and immune checkpoint inhibitors: toward precision medicine against gastrointestinal and hepatobiliary cancers

Abstract

Recent innovations in the next-generation sequencing technologies have unveiled that the accumulation of genetic alterations results in the transformation of normal cells into cancer cells. Accurate and timely repair of DNA is, therefore, essential for maintaining genetic stability. Among various DNA repair pathways, the mismatch repair (MMR) pathway plays a pivotal role. MMR deficiency leads to a molecular feature of microsatellite instability (MSI) and predisposes to cancer. Recent studies revealed that MSI-high (MSI-H) or mismatch repair-deficient (dMMR) tumors, regardless of their primary site, have a promising response to immune checkpoint inhibitors (ICIs), leading to the approval of the anti-programmed cell death protein 1 monoclonal antibody pembrolizumab for the treatment of advanced or recurrent MSI-H/dMMR solid tumors that continue to progress after conventional chemotherapies. This new indication marks a paradigm shift in the therapeutic strategy of cancers; however, when considering the optimum indication for ICIs and their safe and effective usage, it is important for clinicians to understand the genetic and immunologic features of each tumor. In this review, we describe the molecular basis of the MMR pathway, diagnostics of MSI status, and the clinical importance of MSI status and the tumor mutation burden in developing therapeutic strategies against gastrointestinal and hepatobiliary malignancies.

Keywords: Gastric cancer; Hepatocellular carcinoma; Immune checkpoint inhibitor; Microsatellite instability; Pancreatic cancer.

Fig. 1

Schematic diagram of the DNA mismatch repair (MMR) pathway. The MMR pathway involves four steps: mismatch recognition, nicking, excision, and DNA resynthesis/nick ligation. a MutSα (heterodimer of MSH2 and MSH6 proteins) or MutSβ (heterodimer of MSH2 and MSH3 proteins) recognizes and binds to mismatches that occur during DNA replication, and subsequently recruits MutLα (heterodimer of MLH1 and PMS2 proteins). b Proliferating cell nuclear antigen (PCNA) activates MutLα, which makes a DNA nick 5′ to the mismatch. c Exonuclease 1 (EXO1) catalyzes the excision of the nascent DNA strand up to and slightly beyond the mismatch. d The DNA excision gap is re-synthesized by polymerase δ (Polδ) and the remaining nick is sealed by DNA ligase I

Fig. 2

Schematic diagram of microsatellite stability (MSS) and microsatellite instability-high or mismatch repair deficiency (MSI-H/dMMR). a DNA polymerase initiates replication at microsatellite sequences (cytosine/adenine [CA] × 6 repeats). b The CA repeat is wrongly incorporated into the chain of replicated DNA due to DNA polymerase slippage during replication. c When DNA mismatch repair is intact, the replication error is repaired and MSS is maintained. d In mismatch repair deficiency, failure of elimination of the incorrectly incorporated CA repeat leads to the instability of microsatellite lesions (CA × 7 repeats)

Fig. 3

Difference in the response to immune checkpoint therapy between microsatellite-stable (MSS) tumors and microsatellite instability-high or mismatch repair deficiency (MSI-H/dMMR) tumors. High mutation burden (rhombuses) in MSI-H/dMMR tumor leads to the synthesis of mutation-associated neoantigens (small circles) presented by major histocompatibility complex (MHC) class I molecules, which attracts cytotoxic T lymphocytes to the tumor microenvironment via T cell receptor (TCR) engagement with MHC. Blockade of the programmed cell death protein 1 (PD-1)–programmed cell death ligand 1 (PD-L1) interaction with an anti-PD-1 antibody results in T cell activation and infiltration into the tumor, leading to an objective tumor response