Wedding of Molecular Alterations and Immune Checkpoint Blockade: Genomics as a Matchmaker

The development of checkpoint blockade immunotherapy has transformed the medical oncology armamentarium. But despite its favorable impact on clinical outcomes, immunotherapy benefits only a subset of patients, and a substantial proportion of these individuals eventually manifest resistance. Serious immune-related adverse events and hyperprogression have also been reported. It is therefore essential to understand the molecular mechanisms and identify the drivers of therapeutic response and resistance. In this review, we provide an overview of the current and emerging clinically relevant genomic biomarkers implicated in checkpoint blockade outcome. US Food and Drug Administration-approved molecular biomarkers of immunotherapy response include mismatch repair deficiency and/or microsatelliteinstability and tumor mutational burden of at least 10 mutations/megabase. Investigational genomic-associated biomarkers for immunotherapy response include alterations of the following genes/associated pathways: chromatin remodeling (ARID1A, PBRM1, SMARCA4, SMARCB1, BAP1), major histocompatibility complex, specific (eg, ultraviolet, APOBEC) mutational signatures, T-cell receptor repertoire, PDL1, POLE/POLD1, and neo-antigens produced by the mutanome, those potentially associated with resistance include b2-microglobulin, EGFR, Keap1, JAK1/JAK2/interferon-gamma signaling, MDM2, PTEN, STK11, and Wnt/Beta-catenin pathway alterations. Prospective clinical trials are needed to assess the role of a composite of these biomarkers to optimize the implementation of precision immunotherapy in patient care.

Automated summary

The development of checkpoint blockade immunotherapy has had a positive impact on clinical outcomes, but some patients show resistance and experience serious immune-related adverse events. Understanding the molecular mechanisms and identifying the drivers of therapeutic response and resistance is crucial in optimizing precision immunotherapy.