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.

ESMO recommendations on microsatellite instability testing for immunotherapy in cancer, and its relationship with PD-1/PD-L1 expression and tumour mutational burden: a systematic review-based approach

“…Genomic analyses have shown that particular mutational signatures can contribute to high TMB independently from MSI status. These include BRCA1/2 (breast cancer genes 1 and 2) and APOBEC deficiency, neoantigen load, ultraviolet rays exposure and mutations affecting TP53 and polymerase e (POLE) (supplementary Figure S2, available at Annals of Oncology online) [7,59,70,[90][91][92][93][94][95].…”

Immune checkpoint inhibitors: The linchpins of modern immunotherapy

“…One of the most active areas of research pertaining to ICIs is the identification of practical, consistent biomarkers to identify patients likely to respond to therapy. This topic has been comprehensively reviewed recently . The best‐characterized biomarkers based on clinical outcomes are summarized in Figure .…”

“…This topic has been comprehensively reviewed recently. 33,[124][125][126] The best-characterized biomarkers based on clinical outcomes are summarized in Figure 3. The major challenges in identification and validation of biomarkers for response to checkpoint blockade include the complexity and dynamic nature of the immune TME, with significant heterogeneity between tumor subtypes, between individual patients with a subtype, between primary and metastatic sites, and even architecturally within tumor deposits.…”

Bempegaldesleukin (NKTR-214): a CD-122-biased IL-2 receptor agonist for cancer immunotherapy

“…Failure of immune-checkpoint inhibition to induce clinical responses in the majority of cancer patients is due to exclusion of these dendritic cells from the TME (deficiencies in the cGAS-STING pathway); exclusion of T cells (TILs) from the TME; low tumor mutational burden and low PDL1 expression [9,11]. Various immune cells and factors within the TME can also inhibit the therapeutic activities of immune-checkpoint inhibitors, these include Tregs, myeloid-derived suppressor cells (MDSCs), and indole 2,3-dioxygenase (IDO) activity.…”

“…The clinical activity of bempegaldesleukin was consistent with the biological mechanism of biased IL-2 pathway activation, and its ability to increase TILs and increase PD-1 expression on immune cells provides a sound biological basis for combination with anti-PD1 antibodies. Moreover, comparison of anti-PD1-sensitive and anti-PD1-resistant tumors, which paradoxically both contain CD8 + T cells, has suggested that intratumoral Tregs might be responsible for limiting anti-PD1 antibody efficacy in cases where intratumoral T cell numbers appear sufficient, suggesting that selective expansion of T cells/NK cells over Tregs is a viable approach to overcoming anti-PD1 antibody resistance [9,11].…”