The Cancer Epigenome: Exploiting Its Vulnerabilities for Immunotherapy

During cancer initiation and progression, the somatic epigenome is broadly reprogrammed. This reprogramming can be a consequence of several processes, including altered transcriptional profiles and mutations. In addition, immune cells infiltrating the tumor microenvironment display a reprogrammed epigenome. For instance, tumor infiltrating T cells frequently exhibit an exhausted phenotype characterized by aberrant DNA methylation. Moreover, these aberrant epigenomes of cancer cells and infiltrating immune cells may represent a cancer vulnerability. Accumulating evidence supports the potential of using epigenetic therapy to not only reactivate silenced genes in cancer cells, but to also increase antitumor immunogenicity, by reactivation of endogenous retroviruses, to increase tumor immune-infiltration, and to reinvigorate T cell exhaustion. These findings highlight the potential synergies between epigenetic therapies and immunotherapy. Cancer cells and tumor infiltrating immune cells have aberrant epigenomes that present therapeutic opportunities. Epigenetic therapy can reactivate endogenous retroviruses, induce ‘viral mimicry’, and increase tumor immunogenicity. Epigenetic therapy has a potential to reprogram the epigenome of exhausted T cells and re-establish effector functions. Multiple tumor models suggest potential synergies combining epigenetic therapy and immunotherapy to increase antitumor response.