Genomic correlates of response to immune checkpoint blockade

• Published in: Nature medicine Vol. 25; no. 3; pp. 389 - 402
• Main Authors: Keenan, Tanya E., Burke, Kelly P., Van Allen, Eliezer M.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.03.2019; Nature Publishing Group
• Subjects: 631/61/212/2301; 692/699/67/1059/2325; Antigen presentation; Antigen Presentation - genetics; Antigen Presentation - immunology; Antigens, Neoplasm - genetics; Antigens, Neoplasm - immunology; Antineoplastic Agents, Immunological - therapeutic use; B7-H1 Antigen - immunology; Biomarkers; Biomedical and Life Sciences; Biomedicine; Cancer; Cancer immunotherapy; Cancer Research; Carcinogenesis - genetics; Chromatin; Chromatin Assembly and Disassembly - genetics; Correlation; CTLA-4 Antigen - antagonists & inhibitors; CTLA-4 Antigen - immunology; Deoxyribonucleic acid; DNA; DNA Copy Number Variations - genetics; DNA repair; DNA Repair - genetics; Drug Resistance, Neoplasm - genetics; Genome - genetics; Genomics; Humans; Immune checkpoint inhibitors; Immunotherapy; Infectious Diseases; Lymphocytes; Lymphocytes T; Metabolic Diseases; Molecular Medicine; Mutation; Neoantigens; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - immunology; Neurosciences; Patients; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Programmed Cell Death 1 Receptor - immunology; Regulators; Review Article; Signal Transduction; T-Lymphocytes - immunology; Therapeutic targets
• ISSN: 1078-8956; 1546-170X; 1546-170X
• DOI: 10.1038/s41591-019-0382-x

Despite impressive durable responses, immune checkpoint inhibitors do not provide a long-term benefit to the majority of patients with cancer. Understanding genomic correlates of response and resistance to checkpoint blockade may enhance benefits for patients with cancer by elucidating biomarkers for patient stratification and resistance mechanisms for therapeutic targeting. Here we review emerging genomic markers of checkpoint blockade response, including those related to neoantigens, antigen presentation, DNA repair, and oncogenic pathways. Compelling evidence also points to a role for T cell functionality, checkpoint regulators, chromatin modifiers, and copy-number alterations in mediating selective response to immune checkpoint blockade. Ultimately, efforts to contextualize genomic correlates of response into the larger understanding of tumor immune biology will build a foundation for the development of novel biomarkers and therapies to overcome resistance to checkpoint blockade. Responders and non-responders to cancer immunotherapy can be identified through a range of genomic markers.