Rewriting History: Epigenetic Reprogramming of CD8+ T Cell Differentiation to Enhance Immunotherapy

Epigenetic programs are increasingly being used to define the differentiation status of mammalian CD8+ T cells. Developmentally permissive CD8+ T cells have correlated with clinical responses to ICB and CAR T cell therapy in certain cancers. Modification of epigenetic programs in experimental systems and clinical settings have documented that epigenetic engineering approaches can enhance or potentiate existing T cell-based immunotherapies. The full potential of T cell-based immunotherapies remains limited by a variety of T cell extrinsic and intrinsic immunosuppressive mechanisms that can become imprinted to stably reduce the antitumor ability of T cells. Here, we discuss recent insights into memory CD8+ T cell differentiation and exhaustion and the association of these differentiation states with clinical outcomes during immune checkpoint blockade and chimeric antigen receptor (CAR) T cell therapeutic modalities. We consider the barriers limiting immunotherapy with a focus on epigenetic regulation impeding efficacy of adoptively transferred T cells and other approaches that augment T cell responses such as immune checkpoint blockade. Furthermore, we outline conceptual and technical breakthroughs that can be applied to existing therapeutic approaches and to the development of novel cutting-edge strategies. The full potential of T cell-based immunotherapies remains limited by a variety of T cell extrinsic and intrinsic immunosuppressive mechanisms that can become imprinted to stably reduce the antitumor ability of T cells. Here, we discuss recent insights into memory CD8+ T cell differentiation and exhaustion and the association of these differentiation states with clinical outcomes during immune checkpoint blockade and chimeric antigen receptor (CAR) T cell therapeutic modalities. We consider the barriers limiting immunotherapy with a focus on epigenetic regulation impeding efficacy of adoptively transferred T cells and other approaches that augment T cell responses such as immune checkpoint blockade. Furthermore, we outline conceptual and technical breakthroughs that can be applied to existing therapeutic approaches and to the development of novel cutting-edge strategies. cell surface protein identified on T cells at distinct stages of differentiation during the development of T cell exhaustion. subset of memory T cells expressing CD62L and CCR7; able to recirculate between the blood and secondary lymphoid organs. form of immunotherapy whereby T cells are engineered to express an antibody-derived surface fragment specific for a particular antigen associated with a tumor or pathogen, subsequently transferred into the afflicted individual to treat the disease. cell surface receptor serving to repress the T cell effector response when ligated, often described as an immune checkpoint. epigenetic modification whereby a methyl group is added to a DNA base, most commonly observed at cytosines in mammalian cells; can result in changes in transcriptional activity when occurring at promoter of enhancer elements. subset of memory T cells lacking CD62L and CCR7; generally excluded from secondary lymphoid organs and able to circulate between the blood and peripheral tissues. cells that have recently or is actively engaged with its cognate antigen and is now expressing effector molecules. covalent modifications to DNA and/or histones that can impact on chromatin accessibility and ultimately reinforce cell type-specific gene expression programs. therapeutic procedure involving the infusion of antibodies capable of blocking ligand–receptor interactions of inhibitory receptors such as CTLA-4 and PD-1 on T cells. therapeutic modalities utilizing the endogenous immune system, or adoptive transfer of immune cells into a host, to eliminate diseased cells or pathogens. KLRG-1–CD127+ cells forming in the acute phase of an infection, capable of persisting in the long-term; give rise to long-lived memory cells. cells that have exited thymic selection but has not yet undergone antigen-driven differentiation. cell surface receptor serving to repress the T cell effector response when ligated, often described as an immune checkpoint. bears properties allowing their development into other effector and memory T cell subsets. KLRG-1+CD127– activated cells forming in the acute phase of an infection with potent effector functions, but committed to die following the removal of the infected target. differentiation state of T cells induced by persistent antigen stimulation; results in a functional impairment of the cell; can be reinforced by epigenetic modifications. novel index based on the DNA methylation status of T cells; assigns a score ranging from 0 to 1, predictive of the general differentiation status of the T cell. among a group of transcription factors associated with the Wnt signaling pathway that contribute to the preservation of the multipotent developmental potential of T cells.