Genomic Approaches to Understanding Response and Resistance to Immunotherapy

Abstract

Immunotherapy has led to a paradigm shift in the treatment of some malignancies, providing long-term, durable responses for patients with advanced cancers. However, such therapy has benefited only a subset of patients, with some patients failing to respond to treatment at all, and others achieving a limited response followed by tumor progression. Understanding factors contributing to an effective response and further elucidating mechanisms of resistance will be crucial as these therapies are applied more broadly. Genomics-based approaches have significantly advanced the study of response and resistance to immunotherapy in general, and to immune checkpoint blockade more specifically. Here, we review how genomic and transcriptomic approaches have identified both somatic and germline positive correlates of response, including high mutational / neoantigen load, and low intratumoral heterogeneity, among others. The genomic analysis of resistant tumors has additionally identified crucial factors involved in resistance to immune checkpoint blockade, including loss of PTEN and upregulation of other immune checkpoints. Overall, the continued use of genomic techniques at the point of care, combined with appropriate functional studies, would ideally lead to a better understanding of why certain patients respond to immune-based therapies, allowing clinicians to identify the subset of patients likely to benefit from such therapy, and potentially providing insight into how other therapies may be added in combination to increase the number of patients who may benefit from immunotherapy.

Trial watch: Immunogenic cell death induction by anticancer chemotherapeutics

“…C or CD8 C T cells, amongst others; [251][252][253] (2) the circulating levels of multiple cytokines, such as interferon, gamma (IFNG; best known as IFN-g), 254 IL6, 255 and tumor necrosis factor (TNF); 256-258 (3) the amounts of TAA-specific T cells (via tetramer assays); 259,260 (4) the tumor mutational load and/or the abundance of predicted neo-antigens (via genome or whole-exome sequencing); 115,138,[261][262][263][264][265] and (5) the levels of circulating biomarkers of ICD (via proteomic or metabolomic assays).…”

Tissue-Specific Immunoregulation: A Call for Better Understanding of the “Immunostat” in the Context of Cancer

“…From the tumor cell perspective, those patients most likely to benefit appear to have a higher burden of somatic mutations. A "higher mutational load" is thought to generate a more robust antitumor immune response due to a higher probability of the generation of neoepitopes that facilitate T-cell recognition (8,9). Consistent with this concept, anti-PD-1 antibodies have recently been approved for the treatment of cancers with microsatellite instability (MSI), a condition of genetic hypermutability that results from impaired DNA mismatch repair (10).…”

Novel regulators of PD-L1 expression in cancer: CMTM6 and CMTM4—a new avenue to enhance the therapeutic benefits of immune checkpoint inhibitors

“…Development of therapeutic antibodies that inhibit PD-1/PD-L1 pathway (immune checkpoint inhibitors) seems to be a promising tool in terms of clinical benefits and overall patients' survival (11). However, cancer cells frequently manipulate PD-1/PD-L1 axis to evade immune surveillance (3,12).…”

“…However, cancer cells frequently manipulate PD-1/PD-L1 axis to evade immune surveillance (3,12). Therefore, only a subset of patients respond to these agents and fewer still achieve a durable response (11).…”

“…Understanding the mechanisms contributing to an effective response and resistance are of utmost importance to optimize treatment with immune checkpoint inhibitors (11,18). In this context, two potential pathways (CMTM6 and CMTM4), considered as PD-L1 regulators, have been recently discovered in maintaining antitumor immunity (19,20 (19,20).…”