Challenges and Therapeutic Opportunities in the dMMR/MSI-H Colorectal Cancer Landscape

Abstract

About 5 to 15% of all colorectal cancers harbor mismatch repair deficient/microsatellite instability-high status (dMMR/MSI-H) that associates with high tumor mutation burden and increased immunogenicity. As a result, and in contrast to other colorectal cancer phenotypes, a significant subset of dMMR/MSI-H cancer patients strongly benefit from immunotherapy. Yet, a large proportion of these tumors remain unresponsive to any immuno-modulating treatment. For this reason, current efforts are focused on the characterization of resistance mechanisms and the identification of predictive biomarkers to guide therapeutic decision-making. Here, we provide an overview on the new advances related to the diagnosis and definition of dMMR/MSI-H status and focus on the distinct clinical, functional, and molecular cues that associate with dMMR/MSI-H colorectal cancer. We review the development of novel predictive factors of response or resistance to immunotherapy and their potential application in the clinical setting. Finally, we discuss current and emerging strategies applied to the treatment of localized and metastatic dMMR/MSI-H colorectal tumors in the neoadjuvant and adjuvant setting.

Keywords: colorectal cancer; immunotherapy; microsatellite instability; mismatch repair.

Figure 1

Molecular features of immune infiltrated or immune excluded dMMR/MSI-H CRC. Immune infiltrated tumors are characterized by increased PD-L1 and CTLA-4 expression as well as elevated neoantigen presentation. Immune excluded tumors feature a TGF-beta enriched tumor microenvironment with abundant immunosuppressive myeloid cells and fibroblasts. Arrow in blue box means increased. dMMR: deficient mismatch repair. MSI-H: high microsatellite instability. PD-L1: programmed death ligand 1. CTLA-4: cytotoxic T-lymphocyte antigen. MHC I: major histocompatibility complex 1. TIGIT: T cell immunoglobulin and ITIM domain. TMB: tumor mutational burden. CMS1: consensus molecular subtype 1.