Epigenetic Mechanisms of Resistance to Immune Checkpoint Inhibitors

Abstract

Immune checkpoint inhibitors (ICIs) have demonstrated to be highly efficient in treating solid tumors; however, many patients have limited benefits in terms of response and survival. This rapidly led to the investigation of combination therapies to enhance response rates. Moreover, predictive biomarkers were assessed to better select patients. Although PD-L1 expression remains the only validated marker in clinics, molecular profiling has brought valuable information, showing that the tumor mutation load and microsatellite instability (MSI) status were associated to higher response rates in nearly all cancer types. Moreover, in lung cancer, EGFR and MET mutations, oncogene fusions or STK11 inactivating mutations were associated with low response rates. Cancer progression towards invasive phenotypes that impede immune surveillance relies on complex regulatory networks and cell interactions within the tumor microenvironment. Epigenetic modifications, such as the alteration of histone patterns, chromatin structure, DNA methylation status at specific promoters and changes in microRNA levels, may alter the cell phenotype and reshape the tumor microenvironment, allowing cells to grow and escape from immune surveillance. The objective of this review is to make an update on the identified epigenetic changes that target immune surveillance and, ultimately, ICI responses, such as histone marks, DNA methylation and miR signatures. Translational studies or clinical trials, when available, and potential epigenetic biomarkers will be discussed as perspectives in the context of combination treatment strategies to enhance ICI responses in patients with solid tumors.

Prognostic and Predictive Biomarkers in Non-Small Cell Lung Cancer Patients on Immunotherapy—The Role of Liquid Biopsy in Unraveling the Puzzle

“…They studied differentially methylated regions overlapping promoters (pDMRs) or enhancers (eDMRs) in tissue biopsies between responders and non-responders to immunotherapy. Interestingly, they identified 1.007 pDMRs and 607 eDMRs which were associated with the anti-PD-1 response [ 78 , 79 ].…”

“…Furthermore, hypomethylated pDMRs of the Cytohesin 1 Interacting Protein (CYTIP) and the TNF superfamily member 8 (TNFSF8) could predict response in NSCLC patients on anti-PD-1 therapy. In fact, the authors even suggested that their ability to predict the clinical outcome was superior to that of the commonly used biomarker PD-L1 [ 78 , 79 ].…”

Recent Advances in Cancer Immunotherapy

“…This was rapidly followed by the development of monoclonal antibodies targeting another immune checkpoint molecule, PD-1, and its ligand PD-L1 [ 2 ]. These anti-PD-1 (nivolumab and pembrolizumab) and anti-PD-L1 agents (atezolizumab, durvalumab, and avelumab) have shown dramatic and durable response in clinical trials and have now become some of the most widely prescribed anticancer drugs for a wide range of malignancies including non-small cell lung cancer, melanoma, cutaneous squamous cell carcinoma, urothelial carcinoma, cervical cancer, Hodgkin’s lymphoma, head and neck squamous cell carcinoma, Merkel cell carcinoma, renal cell carcinoma, MSI-H or dMMR colorectal cancer, and hepatocellular carcinoma [ 3 ]. Furthermore, chimeric antigen receptor (CAR) T cell therapies have recently joined the list of approved cancer immunotherapies as treatments for mantle cell lymphoma or certain types of large B-cell lymphoma.…”

“…(iii) Exploration for the inherent and acquired resistance mechanisms to cancer immunotherapies is also an important topic. In this Special Issue, two groups independently summarized the resistance mechanisms to checkpoint inhibitors in solid tumors [ 3 , 8 ]. Koustas et al summarized the pan-cancer data for the resistance mechanisms to ICIs that include roles of the tumor microenvironment and autophagy, as well as genetic and epigenetic alterations (such as PTEN loss, JAK1/2 mutations, or microphthalmia-associated transcription factor suppression).…”

“…The second paper, written by Perrier et al, focused on the epigenetic changes (modifications of histones, DNA methylation, and miRNAs) that are related to ICI resistance. The authors also provide a useful summary of miRNAs that regulate PD-L1 expression in many types of cancer cells (see Table 2 in their study) [ 3 ].…”