Epigenetic Regulation of Immunotherapy Response in Triple-Negative Breast Cancer

SIMPLE SUMMARY: Triple-negative breast cancer (TNBC) outcomes are improving since the implementation of immunotherapy. However, objective response rates are still limited to a select group of patients. This is partly due to TNBC intrinsic immune evasive mechanisms and the lack of proper tumor microenvironment immune system activation. Dynamic epigenetic modifications contribute to immune surveillance and immune escape in cancer and can be reverted through epigenetic drugs. This review summarizes the epigenetic changes in TNBC cells and their contribution to the cancer cell–immunity cycle. Furthermore, it also describes how epigenetic drugs may provide novel biomarkers for immunotherapy and enhance the immune response. This manuscript lists the current clinical trials using epigenetic drugs alone or combined with either immune checkpoint inhibitors or small molecules. ABSTRACT: Triple-negative breast cancer (TNBC) is defined by the absence of estrogen receptor and progesterone receptor and human epidermal growth factor receptor 2 (HER2) overexpression. This malignancy, representing 15–20% of breast cancers, is a clinical challenge due to the lack of targeted treatments, higher intrinsic aggressiveness, and worse outcomes than other breast cancer subtypes. Immune checkpoint inhibitors have shown promising efficacy for early-stage and advanced TNBC, but this seems limited to a subgroup of patients. Understanding the underlying mechanisms that determine immunotherapy efficiency is essential to identifying which TNBC patients will respond to immunotherapy-based treatments and help to develop new therapeutic strategies. Emerging evidence supports that epigenetic alterations, including aberrant chromatin architecture conformation and the modulation of gene regulatory elements, are critical mechanisms for immune escape. These alterations are particularly interesting since they can be reverted through the inhibition of epigenetic regulators. For that reason, several recent studies suggest that the combination of epigenetic drugs and immunotherapeutic agents can boost anticancer immune responses. In this review, we focused on the contribution of epigenetics to the crosstalk between immune and cancer cells, its relevance on immunotherapy response in TNBC, and the potential benefits of combined treatments.