Opportunities and challenges of immunotherapy for dMMR/MSI-H colorectal cancer.

Abstract

Colorectal cancer (CRC) with mismatch-repair deficiency (dMMR) is a distinct molecular subgroup of tumors that is characterized by a diminished capacity to correct base-pair mismatches in DNA, which leads to changes in microsatellite sequences and results in high microsatellite instability (MSI-H) accompanied by hypermutation 1 . The incidence of dMMR/ MSI-H in patients with CRC has been reported to be 15% (12% with sporadic disease and 3% with Lynch syndrome). The incidence varies by stage, with 20% in stage II, 10%–15% in stage III, and 3%–5% in stage IV 2 . Despite the presence of numerous neoantigens that promote tumor-infiltrating lymphocytes in the microenvironment, dMMR/MSI-H CRC also exhibits significantly increased expression of immune checkpoints, such as PD-1 and CTLA-4 3 . Immune checkpoint inhibitor (ICI) therapy has been shown to have high sensitivity for dMMR/MSI-H metastatic CRC (mCRC). Additionally, promising results have been obtained in several trials involving locally advanced dMMR/MSI-H CRC. As the search of ICIs for dMMR/MSI-H CRC treatment continues, clinical practice faces numerous opportunities and challenges ( Figure 1 ).