How metabolism bridles cytotoxic CD8+ T cells through epigenetic modifications

Abstract

In the direct competition for metabolic resources between cancer cells and tumor-infiltrating CD8⁺ T cells, the latter are bound to lose out. These effector lymphocytes are therefore rendered exhausted or dysfunctional. Emerging insights into the mechanisms of T cell unresponsiveness in the tumor microenvironment (TME) point towards epigenetic mechanisms as crucial regulatory factors. In this review, we discuss the effects of characteristic components of the TME, i.e. glucose/amino acid dearth with elevated levels of reactive oxygen species (ROS), on DNA methylation and histone modifications in CD8⁺ T cells. We then take a closer look at the translational potential of epigenetic interventions that aim to improve current immunotherapeutic strategies, including the adoptive transfer of T cell receptor (TCR) or chimeric antigen receptor (CAR) engineered T cells.

Figure 1.. Relationship between immunometabolism, oxygen, and epigenetics.

Numerous metabolic intermediates as well as oxygen availability affect the cellular epigenome. The effects of hypoxia are indicated in orange. Abbreviations: 2-HG, 2-hydroxyglutarate; a-KG, α-ketoglutarate; ATP, adenosine triphosphate;; b-OHB, β-hydroxybutyric acid; DNMT, DNA methyltransferases; GLS, glutaminase; GLUD1, glutamate dehydrogenase 1; HAT, histone acetyl transferase; Hcy, homocysteine; HDAC, histone deacetylases; HMT, histone methyltransferases; JmjC, Jumonji N/C terminal domains; LDHA, lactate dehydrogenase A; LSTase, lysine succyniltransferase; NAD⁺/NADH, nicotinamide adenine dinucleotide; NAM, nicotinamide; O₂^-, superoxide; oxphos, oxidative phosphorylation; SAH, S-adenosylhomocysteine; SAM, S-adenosyl-methionine; SIRT, sirtuin; TCA, tricarboxylic acid; TET, ten-eleven translocation methylcytosine dioxygenases

Figure 2.. Explored therapeutic interventions based on epigenetic modifications

The diagram depicts the generation of superior anti-tumor CD8⁺ T cell grafts for adoptive cell transfer (ACT) (left), and targeting (tumor-infiltrating) CD8⁺ T cells in vivo (right). The remaining challenges with ACT, both at the level of efficacy and at the level of toxicity, might potentially be solved with epigenetic drugs (epidrugs). In vivo, epidrugs might also be at the center of reinvigorating the adaptive immune response, overcoming tumor immune escape, and resistance to therapy. Note. Data on the effects of JQ1 are not unequivocal, (designated by ‘?’) Abbreviations: DNMT, DNA methyltransferases; HDAC, histone deacetylase; miRNA, microRNA; TET, ten-eleven translocation