The emerging role of epigenetic therapeutics in immuno-oncology

Abstract

The past decade has seen the emergence of immunotherapy as a prime approach to cancer treatment, revolutionizing the management of many types of cancer. Despite the promise of immunotherapy, most patients do not have a response or become resistant to treatment. Thus, identifying combinations that potentiate current immunotherapeutic approaches will be crucial. The combination of immune-checkpoint inhibition with epigenetic therapy is one such strategy that is being tested in clinical trials, encompassing a variety of cancer types. Studies have revealed key roles of epigenetic processes in regulating immune cell function and mediating antitumour immunity. These interactions make combined epigenetic therapy and immunotherapy an attractive approach to circumvent the limitations of immunotherapy alone. In this Review, we highlight the basic dynamic mechanisms underlying the synergy between immunotherapy and epigenetic therapies and detail current efforts to translate this knowledge into clinical benefit for patients.

Fig. 1 |. Effects of epigenetic therapy on the immune state of a tumour and rationale for the use of combination epigenetic and immunotherapy strategies in cancer.

Epigenetic therapy has the potential to convert a tumour from an immune repressive (immune cold) to an immune permissive (immune hot) state through effects on several factors of the tumour microenvironment that normally impede the therapeutic activity of immune-checkpoint inhibition. Immune cold tumours are characterized by the absence of tumour-infiltrating lymphocytes, the presence of immunosuppressive cell populations, such as tumour-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs), and/or a lack of expression of programmed cell death 1 ligand 1 (PD-L1) by the tumour cells^,. Epigenetic agents can modulate the immune composition of the tumour microenvironment by decreasing the abundance of TAMs and MDSCs and increasing the numbers of CD8⁺ effector T cells and memory T cells^,. As well as having the potential to shift the differentiation of CD8⁺ tumour-infiltrating lymphocytes towards effector and/or memory phenotypes, epigenetic drugs can augment innate immune-related signalling and the expression of inflammatory proteins, such as chemokines^–,,,, which aid the recruitment of T cells to the tumour. In addition, epigenetic therapy can revert key aspects of cancer immunoediting via increased expression of tumour antigens, such as cancer/testis antigens (CTAs)^–, and restoration of the MHC class I (MHC I) antigen processing and presentation machinery (which is often dysregulated in tumour cells)^–,,, thus potentiating the immune recognition of tumours. Type I interferon (IFN) signalling is a major node of these immunological pathways and can be triggered in response to increased levels of cytoplasmic viral RNAs resulting from epigenetic de-repression of endogenous retroviruses (ERVs)^,. Epigenetic therapy can also induce the repression of MYC and MYC-related signalling, thus counteracting the immunosuppressive functions of this oncogenic transcription factor, which include downregulation of type I IFN-mediated gene expression, for example, of the gene encoding the T cell-attracting chemokine CC-chemokine ligand 5 (CCL5); production of CCL9 that recruits immunosuppressive, PD-L1-positive macrophages to tumours and IL-23 that results in exclusion of T cells, natural killer cells and B cells (not shown); and upregulation of inhibitory immune-checkpoint proteins PD-L1 and CD47 in tumour cells, which suppress T cell activation and macrophage-mediated phagocytosis, respectively^,. All of the above contribute to the activity of epigenetic agents in converting immune cold tumours into immune hot tumours, such that the tumours become amenable to immunotherapeutic interventions. For example, the effectiveness of immune-checkpoint inhibitors (ICI) in unleashing an effective T cell-mediated immune response is likely to be enhanced in the context of re-establishment of effective antigen-presentation mechanisms, upregulation of PD-L1, a decreased abundance of TAMs, and increases in the numbers of effector and/or memory T cells within the tumour microenvironment. CTLA-4, cytotoxic T lymphocyte antigen 4; PD-1, programmed cell death 1; SIRPα, signal-regulatory protein a; TCR, T cell receptor; T_H1 cell, type 1 T helper cell.

Fig. 2 |. Implications of DNA methylation-associated programmes on T cell differentiation.

T cell activation from the naive to an effector state is induced by interaction between the T cell receptor (TCR) and corresponding MHC class II–peptide complex on professional antigen-presenting cells or MHC class I in the setting of dendritic cell cross presentation (the context shown in the figure) in concert with co-stimulatory molecule interactions and inflammatory stimuli. Bone marrow-derived antigen-presenting cells — predominantly dendritic cells but also macrophages or B cells — are sufficient to induce CD8⁺ T cell priming, whereas CD4⁺T cells are unable to facilitate this process. As elucidated in studies by Youngblood et al. and Ghoneim et al., among others, the methylation status of genes encoding several crucial mediators of T cell differentiation undergoes dynamic changes during the acquisition of major T cell phenotypes. For example, the transition from a naive to effector phenotype is characterized by the induction and repression of many distinguishing cell-surface markers, including the G protein-coupled chemokine receptors CXC-chemokine receptor 3 (CXCR3) and CC-chemokine receptor 7 (CCR7) and the inhibitory immune-checkpoint receptor programmed cell death 1 (PD-1). CXCR3 expression has been shown to be epigenetically regulated in antigen-specific CD4⁺ T cells, although it remains unclear whether the same is true in CD8⁺ T cells, and renders effector T cells responsive to interferon-inducible, type 1 T helper (T_H1) cell-associated chemokines, such as CXC-chemokine ligand 9 (CXCL9), CXCL10 and CXCL11, which tend to emanate from sites of inflammation. Augmentation of PD-1 expression through demethylation of the PDCD1 (PD-1) gene promoter and a regulatory region ~300 bp upstream of the transcription start site occurs rapidly following antigen stimulation of naive T cells as the direct result of activatory signalling from the TCR^,. PD-1 signalling acts as a negative feedback regulator of the inflammatory activity of T cells by inhibiting TCR-mediated signalling. Cell-surface expression of the homing receptor CCR7 is also dynamically regulated during the naive to effector phenotypic transition via DNA methylation and thus repression of the CCR7 gene^,. CCR7 facilitates the recruitment of naive T cells from the bloodstream to lymphoid organs; therefore, downregulation of this receptor enables primed effector T cells to migrate from these organs to other tissues in surveillance of their cognate antigen. In addition, effector T cells have an increase in methylation and thus repression of TCF7, which encodes transcription factor 7, as well as a loss of methylation and de-repression of IFNG, which encodes the inflammatory cytokine IFNγ. The post-effector fate of CD8⁺T cell generally involves the acquisition of either of two major phenotypes, namely exhausted or memory. The exhausted state is characterized by whole-genome gains in DNA methylation, including sites in TCF7, IFNG and CCR7 (REF). These methylation gains result in reduced effector functionality in terms of both cytolytic activity and cell proliferation. In comparison with effector T cells, exhausted T cells have increased PD-1 expression and decreased CXCR3 expression, which act to sensitize T cells to inhibitory interactions with programmed cell death 1 ligand 1 and prevent chemotactic responses to (T_H1) cell-associated chemokines, respectively. The acquisition of the memory phenotype in effector T cells is correlated with the demethylation and thus re-expression of CCR7 (REF.), with retention of CXCR3 and PD-1 expression^–. Memory T cells demonstrate increased IFNG methylation compared with that associated with the effector state, but do not demonstrate the high methylation levels of this gene found in naive or exhausted CD8⁺ T cells^,. The T cell populations that seem to be most amenable to modulation with epigenetic therapies are those in the post-effector states of T cell differentiation (boxed area)^,.