Immunotherapy efficacy on mismatch repair-deficient colorectal cancer: From bench to bedside

Abstract

Colorectal cancers (CRCs) with deficient mismatch repair (dMMR) or microsatellite instability-high (MSI-H) often have sustained responses to immune checkpoint inhibitors (ICIs) including selective monoclonal antibodies against Program Death 1 (PD-1), Programmed Death Ligand 1(PD-L1), and cytotoxic T lymphocyte associated antigen 4 (CTLA-4). However, a substantial fraction of dMMR CRCs do not respond or ultimately develop resistance to immunotherapy. The majority (~85%) of CRCs are MMR proficient (pMMR) or microsatellite stable (MSS) and lack response to ICIs. Understanding the biology and mechanisms underlying dMMR-associated immunogenicity is urgently needed for improving the therapeutic efficacy of immunotherapy on CRC. Compared to pMMR/MSS CRCs, dMMR/MSI CRCs typically have increased tumor mutational burden (TMB), lower response rate to 5-fluorouracil-based chemotherapy, distinctive immunological features such as high tumor-infiltrating lymphocytes (TILs), and better prognosis. Here, we review the current understanding of the clinical relevance of dMMR/MSI in CRCs, the molecular basis and rationales for targeting dMMR CRC with immunotherapy, and clinical approaches using ICIs as single agents or in combination with other therapies for MSI-H CRCs. Furthermore, we address the potential strategies to sensitize pMMR/MSS CRC to immunotherapy by converting an immunologically "cold" microenvironment into a "hot" one.

Keywords: Colorectal cancer; Combination therapy; Immune checkpoint inhibitors; Immunotherapy; Microsatellite instability; Mismatch repair deficiency.

Fig. 1.

A. Mechanism of DNA mismatch repair (MMR). There are five key MMR proteins in mammalian cells including MSH2, MSH3, MSH6, MLH1, and PMS2. These proteins form heterodimer complexes to recognize and correct erroneous insertion, deletion, and misincorporation of bases that arise during DNA replication, DNA recombination, and some forms of DNA damage. B. Analysis of microstate instability (MSI). MSI can be assayed by PCR amplification of microsatellites followed by analysis of PCR product size. Due to DNA polymerase slippage in reading through repetitive sequences, PCR amplification of microsatellites typically generates multiple peaks on a sequencing gel. MSI is indicated by a shift in PCR produce size (blue peaks) relative to a microsatellite stable (MSS) sample (red peaks).

Fig. 2.

Comparison between dMMR/MSI-H and pMMR/MSS colorectal cancers. dMMR/MSI-H CRCs have a high mutational burden and persistent renewal of neoantigens, which is favorable for immune surveillance, while pMMR/MSS CRCs have a low mutational burden and lack immune surveillance.

Fig. 3.

ICI therapy for targeting dMMR/MSI-H and pMMR/MSS CRCs. ICI therapy is effective for a subset of dMMR/MSI-H CRCs by triggering an antitumor immune response. Combinations of different ICIs and ICIs with chemotherapy, radiotherapy, targeted therapy, vaccines, or other immune agents may convert “cold” tumors into “hot” and are potentially effective for insensitive dMMR/MSI-H CRCs and most of pMMR/MSS CRCs.