Immune checkpoint inhibitors for the treatment of MSI-H/MMR-D colorectal cancer and a perspective on resistance mechanisms

Cet article passe en revue les études mettant en évidence l'efficacité des inhibiteurs de point de contrôle immunitaire chez les patients atteints d'un cancer colorectal métastatique avec forte instabilité des microsatellites et déficience du système de réparation des mésappariements de l'ADN, analyse les études évaluant l'association entre des biomarqueurs et la réponse immunitaire, puis examine les mécanismes potentiellement liés à la résistance thérapeutique intrinsèque ou acquise

Résumé en anglais

Metastatic colorectal cancer (CRC) with a mismatch repair-deficiency (MMR-D)/microsatellite instability-high (MSI-H) phenotype carries unique characteristics such as increased tumour mutational burden and tumour-infiltrating lymphocytes. Studies have shown a sustained clinical response to immune checkpoint inhibitors with dramatic clinical improvement in patients with MSI-H/MMR-D CRC. However, the observed response rates range between 30% and 50% suggesting the existence of intrinsic resistance mechanisms. Moreover, disease progression after an initial positive response to immune checkpoint inhibitor treatment points to acquired resistance mechanisms. In this review article, we discuss the clinical trials that established the efficacy of immune checkpoint inhibitors in patients with MSI-H/MMR-D CRC, consider biomarkers of the immune response and elaborate on potential mechanisms related to intrinsic and acquired resistance. We also provide a perspective on possible future therapeutic approaches that might improve clinical outcomes, particularly in patients with actionable resistance mechanisms.