Epigenetic modulation of antitumor immunity for improved cancer immunotherapy

Abstract

Epigenetic mechanisms play vital roles not only in cancer initiation and progression, but also in the activation, differentiation and effector function(s) of immune cells. In this review, we summarize current literature related to epigenomic dynamics in immune cells impacting immune cell fate and functionality, and the immunogenicity of cancer cells. Some important immune-associated genes, such as granzyme B, IFN-γ, IL-2, IL-12, FoxP3 and STING, are regulated via epigenetic mechanisms in immune or/and cancer cells, as are immune checkpoint molecules (PD-1, CTLA-4, TIM-3, LAG-3, TIGIT) expressed by immune cells and tumor-associated stromal cells. Thus, therapeutic strategies implementing epigenetic modulating drugs are expected to significantly impact the tumor microenvironment (TME) by promoting transcriptional and metabolic reprogramming in local immune cell populations, resulting in inhibition of immunosuppressive cells (MDSCs and Treg) and the activation of anti-tumor T effector cells, professional antigen presenting cells (APC), as well as cancer cells which can serve as non-professional APC. In the latter instance, epigenetic modulating agents may coordinately promote tumor immunogenicity by inducing de novo expression of transcriptionally repressed tumor-associated antigens, increasing expression of neoantigens and MHC processing/presentation machinery, and activating tumor immunogenic cell death (ICD). ICD provides a rich source of immunogens for anti-tumor T cell cross-priming and sensitizing cancer cells to interventional immunotherapy. In this way, epigenetic modulators may be envisioned as effective components in combination immunotherapy approaches capable of mediating superior therapeutic efficacy.

Deciphering the tissue-specific regulatory role of intronless genes across cancers

“…In conclusion, IGs drive massive transcriptional rewiring, as observed in co-expression analysis, that may drive tumorigenesis and may act as novel therapeutic targets for gene therapy and in-silico drug design such as popular GPCRs or emerging HDAC inhibitors [29].…”

Identification of Novel Tumor Antigens and the Immune Landscapes of Bladder Cancer Patients for mRNA Vaccine Development

“…Immune check points (ICP) and immunogenic cell death (ICD) regulators play essential roles in anti-tumor immunity, and may influence the efficacy of immunotherapy and mRNA vaccines (25). To determine the differences between distinct immune subtypes, we comprehensively accessed 43 ICP genes and 25 ICD regulator genes in the GSE13507 and TCGA datasets.…”

Immunogenic cell death‐inducing small molecule inhibitors: Potential for immunotherapy of cancer

“…SMIs for epigenetic enzymes function in part through ICD induction and improved antitumor immune responses and thus potentiate immunotherapy of cancer. 4 It will be even better if an SMI can induce multimodal cell death, as one or more modes of death will likely be ICD and thus potentiate antitumor immunity. As discussed, SMIs for APE1 (No.0449-0145), 7 BI and CPT, 8 belong to this group of SMIs targeting multiple cell death pathways leading to ICD, and thus they enhance antitumor immunity.…”

“…Recently approved Lumakras, the SMI of KRAS G12C , works in part by inducing inflammation of the tumour tissues and eliciting antitumor immunity. SMIs for epigenetic enzymes function in part through ICD induction and improved antitumor immune responses and thus potentiate immunotherapy of cancer 4 . It will be even better if an SMI can induce multimodal cell death, as one or more modes of death will likely be ICD and thus potentiate antitumor immunity.…”