Epigenetic Regulation of Immunotherapy Response in Triple-Negative Breast Cancer

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.

Keywords: TNBC; breast cancer; cancer; epigenetic drugs; epigenetics; immune checkpoint; immune system; immunotherapy.

Figure 1

Overview of epigenetics. Gene regulatory elements (GRE) are defined according to their location and effect on the associated gene expression. Promoters are located close to the transcription start site of their associated genes and facilitate the transcription machinery deposition. This deposition can be aided or blocked by distant GRE called enhancers and silencers, respectively. Chromatin architecture is dynamically regulated by another group of GRE called insulators, which mediate in the topological associating domains (TADs) formation and further contributing to gene expression. DNA and histone modifications are tightly regulated by three different groups of proteins: writers, which are involved in the deposition of these chemical marks; erasers, which are responsible for removing these modifications; and readers, which can recognize the epigenetic code and recruit other proteins.

Figure 2

Epigenetic regulation of cancer–immunity cycle in TNBC. This scheme shows epigenetic mechanisms involved in TNBC immune escape (brown square in the middle). It also includes the different steps of the cancer immunity cycle. Scheme based on Chen and Mellman (2013) cancer-cell immunity cycle [23]. Abbreviations: CTAs (Cancer testis antigens), TCR (T-cell receptor), MHC (Major Histocompatibility complex).

Figure 3

Therapeutic opportunities combining epigenetics and immunotherapy. Different GRE, including promoters and enhancers, have been identified close to the transcription start site (TSS) of IC-related genes using the Epilogos visualization tool (https://epilogos.altius.org/, accessed on 29 April 2021). A total of 127 human samples from the Roadmap Consortium were considered when cancer cell-expressing genes were interrogated. In contrast, the blood & T cells category was selected from T cell and NK expressing genes.

Figure 4

Epigenetic drugs contribute to turning cold tumors into hot. Cancer cells modulate their microenvironment to promote immune escape, increasing the presence of immunosuppressive cells on the tumor site and becoming a “cold tumor”, which displays a worse response against immunotherapy. Epigenetic drugs may switch this state, enhancing the immune response through the recruitment of CTLs, becoming a “hot tumor”. Hot tumors respond better to immunotherapy.