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

Abstract

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 β2-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.

Figure 1.

US Food and Drug Administration–approved and investigational biomarkers associated with response to immuno-oncology therapy. APOBEC = apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like; ARID1A = AT-rich interaction domain 1A; BAP1 = BRCA1-associated protein 1; MHC-I = major histocompatibility complex class-I; PBRM1 = polybromo-1; PD-L1 = programmed cell death-ligand 1; POLD1 = DNA polymerase delta 1; POLE = DNA polymerase epsilon; SMARCA4 = SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A, member 4; SMARCB1 = SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B, member 1; TMB = tumor mutational burden.

Figure 2.

Investigational biomarkers associated with resistance to immuno-oncology therapy. It is not yet clear if some of these markers, such as KEAP1 and STK11 alterations, are prognostic or predictive. EGFR = epidermal growth factor receptor; JAK = Janus kinase; KEAP1 = Kelch-like ECH associated protein 1; KRAS = v-Ki-ras2 kirsten rat sarcoma viral oncogene homolog; MDM2 = murine double minute 2; PTEN = phosphatase and TENsin homolog deleted on chromosome 10; STK11 = serine/threonine kinase 11.