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Epigenetic mechanisms, including chromatin structure regulation, non-coding RNAs, histone post-translational modifications, and DNA methylation, are essential for the interactions between cancer cells and immune cells. Immune cells depend on the expression of specific cell-surface molecules to recognize and eliminate cancer cells. However, tumor cells can take over various epigenetic mechanisms and subsequently use epigenetic silencing to shut off this crucial expression, thereby escaping the recognition from immune cells. Epigenetic modifiers can also reactivate many silenced genes such as immune checkpoints regulators that turn on immune response.
As a result, in recent years, epigenetic drugs have been a topic of keen interest for clinical researchers. These drugs include promising immunomodulatory agents that may restore expression of cell-surface molecules that allow cancer cells to once again be detectable as well as other targeting agents that trigger antitumor immune responses. Epigenetic therapies, either alone or in combination with current immunotherapies, may lead to new approaches for cancer treatment.
The idea of combination therapy for treating cancers has become especially critical. Many patients either do not respond, become resistant, or suffer toxicities from current immunotherapy treatments alone. The combination of epigenetic therapy with common immunotherapies such as interleukin-2 therapy, adoptive T-cell transfer, and immune checkpoint inhibitors, among others are just a few of the strategies being tested with various cancer types in clinical trials. Researchers have demonstrated that combining epigenetic drugs, such as the DNA methyltransferase inhibitors 5-aza-2′-deoxycytidine and guadecitabine, with immunomodulating antibodies that target CTLA-4 or the PD-1/PDL-1 immune checkpoint improves therapeutic efficacy.
Additionally, epigenomic signatures in immune and cancer cells may be predictors of success of immunotherapy for patients. Candidate epigenetic biomarkers may improve patient classification and personalized medicine to maximize treatment success and minimize negative effects. Potential biomarkers have been identified in the literature as predictors of the cancer response to immunotherapy such as PD-L1 expression, tumor-associated antigens (TAAs), HLA expression , tumor mutational burden and neoantigen identification , mismatch repair deficiency to name a few. The epigenetic control of these events has been validated. Epigenetic biomarkers may offer additional advantages, such as revealing information about the life habits and conditions of patients, details about the origin of the tumors, predictive indicators, and therapy-monitoring indicators.