Molecular and Genomic Determinants of Response to Immune Checkpoint Inhibition in Cancer

Abstract

Molecularly targeted therapy and immunotherapy have dramatically changed the landscape of available treatment options for patients with advanced cancer. Improved understanding of the molecular and genomic features of cancers over the last decade has led to the development of successful targeted therapies and the field of precision cancer medicine. As a result of these advances, patients whose tumors harbor select molecular alterations are eligible for treatment with targeted therapies active against the unique molecular aberration. Concurrently, advances in tumor immunology have led to the development of immunomodulatory antibodies targeting T cell coinhibitory receptors CTLA-4 and PD-1 (programmed death–1) that have shown activity in several cancer histologies, reinvigorating antitumor immune responses in a subset of patients. These immunomodulatory antibodies offer the promise of durable disease control. However, discrete genomic determinants of response to cancer immunotherapy, unlike molecularly targeted therapies, have remained elusive, and robust biomarkers are lacking. Recent advances in tumor profiling have begun to identify novel genomic features that may influence response and resistance to cancer immunotherapy, including tumor mutational burden (e.g., microsatellite instability), copy-number alterations, and specific somatic alterations that influence immune recognition and response. Further investigation into the molecular and genomic features of response and resistance to cancer immunotherapy will be needed. We review the recent advances in understanding the molecular and genomic determinants of response to cancer immunotherapy, with an emphasis on immune checkpoint inhibitors.