Epigenetic: Enhance Patient Response to Immunotherapy

Epigenetics is the study of heritable changes in gene expression (active versus inactive genes) that do not involve changes to the underlying DNA sequence — a change in phenotype without a change in genotype — which in turn affects how cells read the genes. Epigenetic change is a regular and natural occurrence but can also be influenced by several factors including age, the environment/lifestyle, and disease state.

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Epigenetic modifications can manifest as commonly as the manner in which cells terminally differentiate to end up as skin cells, liver cells, brain cells, etc. Or, epigenetic change can have more damaging effects that can result in diseases like cancer. At least three systems including DNA methylation, histone modification and non-coding RNA (ncRNA)-associated gene silencing are currently considered to initiate and sustain epigenetic change. New and ongoing research is continuously uncovering the role of epigenetics in a variety of human disorders and fatal diseases.

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Resistance to immunotherapy in cancers

Immunotherapy protocols are designed to annihilate immune escape in cancer cells and restore elimination of cancer cells. In 2018, Nobel Prize in medicine awarded James P. Allison and Tasuku Honjo for their work on the knowledge of immune edition and the development of immunotherapies to fight against cancer cells. Immunotherapies include: cancer vaccines, humanized monoclonal antibodies targeting TAAs, transfer of chimeric antigen receptor-T-cells or adoptive transfer of transgenic TCR-expressing T-cells. Nevertheless, immunotherapy resistances have been described in patients and are divided in innate and acquired resistance.

Epigenetics includes DNA methylation, histones post-translational modifications and non-coding RNA and regulates gene expression in a transmissible but reversible manner. DNA methylation is processed by DNA methyl transferases (DNMTs) which catalyze the addition of a 5methyl cytosine on the 5th position of cytosines in CpGs. This mark is generally repressive and many genes are normally controlled by DNA methylation during embryogenesis. Aberrant DNA methylation also frequently occurs in pathologies, specifically in cancers, where it contributes to tumor suppressor gene silencing or inactivation of apoptosis.

Histone Modifications

When the chromatin structure is highly compact, the efficient recruitment and processivity of RNA Polymerase II (Pol Il) is impeded and transcription is thus hindered . The dysregulation of histone post-translational modification alters the chromatin structure and induces abnormal gene expression, which is correlated with the occurrence and development of diseases, especially cancers. Modifications of all four histones have been reported, but those affecting H3 and H4 are best understood . Among these histone modifications, the regulatory role and function of acetylation and methylation have been studied most intensively.

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