Beyond Tumor PD-L1: Emerging Genomic Biomarkers for Checkpoint Inhibitor Immunotherapy.

Despite the success of immune checkpoint blockade as a strategy for activating an antitumor immune response and promoting cancer regression, only a subset of patients have durable clinical benefit. Efforts are ongoing to identify robust biomarkers that can effectively predict treatment response to immune checkpoint inhibitors (ICIs). Although PD-L1 expression is useful for stratifying patients, it is an imperfect tool. Comprehensive next-generation sequencing platforms that are readily used in clinical practice to identify a tumor's potentially actionable genetic alterations also reveal tumor genomic features, including tumor mutation burden (TMB), that may impact the response to ICIs. High TMB enhances tumor immunogenicity through increased numbers of tumor neoantigens that may promote an immune response. Defective DNA repair, leading to microsatellite instability, is an endogenous mechanism for increased tumor TMB that augments response to anti-PD-1 blockade. Alternatively, DNA damage from exogenous factors is responsible for high TMB seen in melanoma, lung cancer, and urothelial carcinoma, among tumor subtypes with higher response rates to ICIs. In this review, we summarize data supporting the use of TMB as a biomarker as well as its known limitations. We also highlight specific tumor suppressor genes and oncogenes that are under investigation as biomarkers for ICI response and resistance. Efforts are ongoing to delineate which genomic tumor characteristics can eventually be utilized in clinical practice to ascertain the benefit of ICIs for an individual patient.