Editorial: Genetic and Epigenetic Control of Immune Responses

Cancer, traditionally viewed as a disease driven by genomic alterations, is now perceived as an accumulation of genetic mutations as well as global epigenetic changes to the chromatin that regulate gene expression (1, 2). Genetic alterations to either tumor suppressors or oncogenes can result in dramatic gene expression changes leading to cancer; however, changes in the epigenome are rather subtle. Despite similar genomic sequences in all the cell types, the epigenome can vary considerably, resulting in distinct gene expression patterns and, therefore, distinct cellular functions. Epigenetic modifications to chromatin include DNA methylation, histone modifications, nucleosome positioning, and non-coding RNAs that can regulate access of DNA to transcription factors and other cis-regulatory elements, thereby affecting gene expression (3). It is now recognized that genetic and epigenetic components complement each other to drive tumor initiation and progression (4). Recent technical advances in high throughput sequencing have improved understanding of the epigenomic landscape at a higher resolution. Massive datasets and databases, including the encyclopedia of DNA elements (ENCODE) (5), The Cancer Genome Atlas (TCGA) ((https://www.cancer.gov/tcga), the NIH Roadmap Epigenomics Mapping Consortium (6), the Epigenome browser (7), have enhanced our ability to understand the interplay between cancer cells, tumor microenvironment (TME) and immune cells. Therefore, a new classification of molecular epigenetic modifications is needed to differentiate “cancer intrinsic” and “cancer extrinsic” mechanisms influencing anti-tumor immune responses. The schematic shows a graphical representation of various intrinsic and extrinsic factors affecting the cancer cells and thereby regulate the TME ( Figure 1 ). The International Human Epigenome Consortium (IHEC) provides high-resolution reference epigenomes of major primary human cell types (8). Based on the data from these projects, genetic and epigenetic crosstalk in cells is evident, and it has led to the identification of novel biomarkers and the development of novel therapeutic strategies. The articles in this Research Topic on Genetic and Epigenetic Control of Immune Responses address both cell-intrinsic and cell-extrinsic mechanisms controlling the immune response to tumors. Open in a separate window Figure 1 Tumor intrinsic and extrinsic factors regulating immune responses in the tumor microenvironment. Cancer cell intrinsic factors such as genomic mutations, chromatin modifiers and non-coding RNA regulate tumor initiation, propagation as well as immunogenicity. Epigenetic modifications such as DNA methylation, histone acetylation and methylation regulate gene expression. Non-coding RNA including long non-coding RNA, microRNA, circular non-coding RNA regulate gene transcription as well as mRNA stability. Other mechanisms intrinsic to cancer cells include expression of immunosuppressive cytokines to facilitate escape from anti-tumor immunity, expression of immunosuppressive molecules such as PD-L1 and PD-L2, suppression of antigen processing and presentation machinery and tumor associated antigens. Cancer cell extrinsic factors include tumor infiltrated immune cells, fibroblasts, stromal cells and endothelial cells. Extrinsic factors also include secretory factors such as cytokines, chemokines, metabolites, growth factors and immune checkpoint molecules. Tumor associated antigens presented by antigen presenting cells such as macrophages, dendritic cells activate CD8 T-cells for effective anti-tumor immunity. However, immune checkpoint molecules expressed by cancer cells regulate the inflammatory status of the tumor tamping down the inflammation. Use of epigenetic modifiers such as DNMT inhibitors, HDAC inhibitors, BET inhibitors etc. can alter these reversible modifications to enhance anti-tumor immunity. Figure created with BioRender.com.