Therapeutic Cancer Vaccines-T Cell Responses and Epigenetic Modulation

Abstract

There is great interest in developing efficient therapeutic cancer vaccines, as this type of therapy allows targeted killing of tumor cells as well as long-lasting immune protection. High levels of tumor-infiltrating CD8⁺ T cells are associated with better prognosis in many cancers, and it is expected that new generation vaccines will induce effective production of these cells. Epigenetic mechanisms can promote changes in host immune responses, as well as mediate immune evasion by cancer cells. Here, we focus on epigenetic modifications involved in both vaccine-adjuvant-generated T cell immunity and cancer immune escape mechanisms. We propose that vaccine-adjuvant systems may be utilized to induce beneficial epigenetic modifications and discuss how epigenetic interventions could improve vaccine-based therapies. Additionally, we speculate on how, given the unique nature of individual epigenetic landscapes, epigenetic mapping of cancer progression and specific subsequent immune responses, could be harnessed to tailor therapeutic vaccines to each patient.

Keywords: DNA methylation; T cells; biomarkers; cancer vaccine-adjuvants; epigenetics; histone modifications; long non-coding RNAs; microRNAs.

Figure 1

Failed immunity conditions that can be rescued by therapeutic cancer vaccines. Therapeutic cancer vaccines generate de novo T cell immunity that can repair the conditions that cause the failure of T cell-mediated immunity. These conditions include (1) having a low number of tumor specific T cells due to the lack of tumor antigen presentation and development of immune tolerance, (2) suppression of T cell infiltration into the solid tumor mass due to immunosuppressive microenvironments created by the cancer cells, and (3) T cell dysfunction/exhaustion due to chronic antigen exposure.

Figure 2

T cell activation and differentiation into effector cells and subsequent memory and exhaustion phenotypic changes. Differentiation of naive CD8⁺ T cells to cytotoxic T cells (CTLs) requires three signal interactions with dendritic cells (DCs). These include (1) the engagement of the T cell receptors (TCRs) with antigens as complexes with MHC class I molecules, (2) the interaction of DC costimulatory molecules with their receptors on CD8⁺ T cells, (3) stimulatory cytokines secreted by DCs to activate T cells. Additionally, co-stimulation of CD8⁺ T cells by T helper cells activated by DCs through MHC class II-antigen-TCR and costimulatory molecule complexes are required to promote efficient and durable CTL responses. The differentiation and activation of CD8⁺ T cells could potentially be enhanced by an HDAC inhibitor and miRNA-based therapeutics. Differentiation of naive cells into memory T cells is required for long-lasting protection and can be enhanced by a BET bromodomain inhibitor. Furthermore, upon chronic exposure to antigen, T cells can develop exhaustion phenotype. However, this exhaustion can be counteracted by cancer vaccines that generate de novo T cell immunity. miRNA-based therapeutics could potentially be used to help rejuvenate exhausted T cells.

Figure 3

Cancer immune evasion and the epigenetic modifications counteracting such mechanisms. To escape from immune-mediated killing, cancer cells exploit several evasion strategies. These are (1) downregulation of antigen presentation and costimulatory molecules, which could be counteracted by the inhibitors of epigenetic regulators including DNA methyltransferase (DNMT), histone deacetylase (HDAC), histone acetyltransferase (HAT), or histone demethylase (HDM), (2) downregulation of chemokines that signal T cells to infiltrate tumor mass, again that could be inhibited by inhibitors of DNMT, HDAC, or EZH2, and (3) upregulation of coinhibitory/checkpoint ligands, which could also be blocked by a BET bromodomain inhibitor.