Deficient Mismatch Repair and the Role of Immunotherapy in Metastatic Colorectal Cancer.
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.
College of Osteopathic Medicine, Michigan State University, East Lansing, MI, 48824, USA.
Dionisia
D
Quiroga
Duke Cancer Institute, Durham, NC, 27710, USA.|Department of Surgery, Duke University Medical Center, Durham, NC, 27710, USA.
H Kim
HK
Lyerly
Duke Cancer Institute, Durham, NC, 27710, USA. michael.morse@dm.duke.edu.|Department of Medicine, Duke University Medical Center, DUMC 3233, Durham, NC, 27710, USA. michael.morse@dm.duke.edu.
Michael A
MA
Morse
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor; D019496:Cancer Vaccines / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D053843:DNA Mismatch Repair / Q000187:drug effects / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D056747:Immunomodulation / Q000187:drug effects; D007167:Immunotherapy / Q000379:methods; D053842:Microsatellite Instability; D058990:Molecular Targeted Therapy; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D016896:Treatment Outcome; D019139:Tumor Escape / Q000941:ethics / Q000276:immunology; D059016:Tumor Microenvironment / Q000235:genetics / Q000276:immunology
D014408:Biomarkers, Tumor; D019496:Cancer Vaccines
Colorectal cancer; Immune checkpoint; Immunotherapy; Microsatellite instability; Mismatch repair; Tumor microenvironment