Abstract
Simple SummaryDendritic cells (DCs) are an important type of immune cell present in the blood and tissues, capable of detecting potential threats and displaying them to lymphocytes in the lymph nodes, therefore initiating lymphocyte-mediated responses. DCs not only recognize pathogens but also damaged or altered cells from our own bodies, such as cancer cells, and contribute to the immune response to cancer. However, the tumor microenvironment, the environment that surrounds cancer cells, produces a number of factors that can modulate the function of DCs, which can acquire an immunosuppressive phenotype that allows tumor growth. This acquisition is also tightly regulated by epigenetics, the set of mechanisms that impact gene function without altering the DNA sequence. In this review, we discuss epigenetic mechanisms that influence the development of functional DCs and their altered function in the tumor microenvironment. We propose how this knowledge can be used both to epigenetically modulate these cells, and for the development of DC-based vaccine therapies.Dendritic cells (DCs) are professional antigen-presenting cells with the distinctive property of inducing the priming and differentiation of naïve CD4+ and CD8+ T cells into helper and cytotoxic effector T cells to develop efficient tumor-immune responses. DCs display pathogenic and tumorigenic antigens on their surface through major histocompatibility complexes to directly influence the differentiation of T cells. Cells in the tumor microenvironment (TME), including cancer cells and other immune-infiltrated cells, can lead DCs to acquire an immune-tolerogenic phenotype that facilitates tumor progression. Epigenetic alterations contribute to cancer development, not only by directly affecting cancer cells, but also by their fundamental role in the differentiation of DCs that acquire a tolerogenic phenotype that, in turn, suppresses T cell-mediated responses. In this review, we focus on the epigenetic regulation of DCs that have infiltrated the TME and discuss how knowledge of the epigenetic control of DCs can be used to improve DC-based vaccines for cancer immunotherapy.
Highlights
Efficient immune responses to threats involve a wide range of cell types within the adaptive and innate immune systems
The production of factors released into the tumor microenvironment (TME), such as vascular endothelial growth factor (VEGF), prostaglandin E2 (PGE2), and granulocyte-macrophage colony-stimulating factor (GM-CSF), pro-inflammatory cytokines such as IL-1β, IL-6, and tumor necrosis factor (TNF), and the peptides S100A8 and S100A9, can influence the differentiation of monocytes that arrive in the TME, where they accumulate and bestow a powerful immunosuppressive capacity, which affects their differentiation into monocytederived DCs (moDCs) [150].These cells are typically defined as myeloid-derived suppressor cells (MDSCs) [151], and may serve as a protective mechanism to prevent excessive tissue damage caused by unresolved immune responses [152]
The TME produces a number of factors that can modulate Dendritic cells (DCs) immune response, thereby acquiring an immunosuppressive phenotype that allows tumor growth
Summary
Efficient immune responses to threats involve a wide range of cell types within the adaptive and innate immune systems. These threats include pathogens, self-antigens in autoimmune conditions, and damaged or aberrant cells in cancer. In most cases, tumor-infiltrating DCs develop an immune-tolerant phenotype that favors tumor growth [2,3]. This is in part due to the effects that cancer cells exert on different immune cell types through cell-to-cell contacts, secretion of soluble factors and exosome release, which influence their epigenetic and gene expression profiles. The potential role of epigenetic dysregulation in tumor-infiltrated DCs is highly relevant as a result of the potential pharmacological reversion of epigenetic alterations and immunogenic phenotype, as well as in the context of using these mechanisms for improving DC-based vaccines
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