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Beyond Tumor PD-L1: Emerging Genomic Biomarkers for Checkpoint Inhibitor Immunotherapy
Galina G Lagos1, Benjamin Izar1, Naiyer A Rizvi1
1Columbia University Medical Center, New York, NY.
Abstract:
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.
Insights
Tumor mutation burden (TMB) shows promise as a biomarker for predicting response to immune checkpoint inhibitors (ICIs). Further research is needed to fully utilize genomic features for personalized cancer therapy.
Area of Science:
- Oncology
- Immunology
- Genetics
Background:
- Immune checkpoint blockade (ICB) offers durable clinical benefit in a subset of cancer patients.
- Predictive biomarkers for ICB response, such as PD-L1 expression, have limitations.
- Next-generation sequencing (NGS) provides insights into tumor genomic features impacting ICB efficacy.
Purpose of the Study:
- To review the utility of tumor mutation burden (TMB) as a biomarker for immune checkpoint inhibitor (ICI) response.
- To discuss the limitations of TMB and explore other genomic biomarkers.
- To highlight the potential of genomic characteristics for guiding ICI treatment decisions.
Main Methods:
- Literature review of studies investigating biomarkers for ICI response.
- Analysis of data linking tumor genomic features, including TMB, to ICB efficacy.
- Examination of mechanisms underlying high TMB and its association with treatment outcomes.
Main Results:
- High TMB, driven by endogenous (microsatellite instability) or exogenous factors, enhances tumor immunogenicity and correlates with improved ICI response.
- Specific tumor suppressor genes and oncogenes are emerging as potential biomarkers for ICI response and resistance.
- Tumor subtypes like melanoma, lung, and urothelial carcinoma exhibit higher response rates to ICIs, often associated with high TMB.
Conclusions:
- TMB is a promising biomarker for predicting ICI response, though not without limitations.
- Genomic profiling offers a comprehensive approach to identify patients likely to benefit from ICIs.
- Further research is crucial to integrate genomic biomarkers into clinical practice for personalized cancer immunotherapy.
