Deficient Mismatch Repair and the Role of Immunotherapy in Metastatic Colorectal Cancer.

Abstract

Division of colorectal cancers (CRCs) into molecular subsets yields important consequences for prognosis and therapeutic response. The microsatellite instability (MSI) immune subgroup, accounting for 15% of early-stage and 3% of metastatic CRCs, are a result of deficient cellular DNA mismatch repair (dMMR) mechanisms. dMMR CRCs are notable for greater survivability, yet lack of benefit from fluoropyrimidine-based therapy in early-stage disease as compared to proficient DNA mismatch repair (pMMR) CRCs but are substantially lethal when metastatic. The surging interest in cancer immunotherapy, particularly checkpoint blockade, has further led to a focus on MSI tumors, which are notable for their substantial T cell infiltrate. In this review, we will discuss the biologic underpinnings for the immunogenicity of dMMR CRC and the preclinical development of therapies intended to modulate this immune response. Next, we will discuss the previous and ongoing clinical trials specifically designed to evaluate immunotherapeutic treatment of dMMR CRCs. Building on the success of the early immune checkpoint inhibitor clinical trials for dMMR CRC, combinations with other anti-tumor immunotherapies may provide an even more robust response, thereby, creating an alternative treatment regimen for those who have failed standard therapies or possibly resulting in prophylactic therapies for patients with highly oncogenic hereditary mismatch repair deficiencies.