bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2020–08–09
sixteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Cellular metabolism dictates T cell effector function in health and disease.
  2. Immunometabolism and HIV-1 pathogenesis: food for thought.
  3. The interplay between immunosenescence and age-related diseases.
  4. Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies.
  5. Expression Pattern of Telomerase Reverse Transcriptase (hTERT) Variants and Bcl-2 in Peripheral Lymphocytes of Systemic Lupus Erythematosus Patients.
  6. Multiple developmental pathways lead to the generation of CD4 T cell memory.
  7. Inhibition of Cdc42 activity extends lifespan and decreases circulating inflammatory cytokines in aged female C57BL/6 mice.
  8. Metabolic conditioning of CD8+ effector T cells for adoptive cell therapy.
  9. Mitochondrial Oxidative Damage Underlies Regulatory T Cell Defects in Autoimmunity.
  10. Memory CD8+ T Cells Balance Pro- and Anti-inflammatory Activity by Reprogramming Cellular Acetate Handling at Sites of Infection.
  11. Immunometabolism in the pathogenesis of systemic lupus erythematosus.
  12. Autophagy, the innate immune response and cancer.
  13. Adenosine monophosphate deaminase 3 null mutation causes reduction of naive T cells in mouse peripheral blood.
  14. Metabolic communication during exercise.
  15. Nicotine Changes the microRNA Profile to Regulate the FOXO Memory Program of CD8+ T Cells in Rheumatoid Arthritis.
  16. Role of Epigenetic Modifications in Inhibitory Immune Checkpoints in Cancer Development and Progression.
  1. Scand J Immunol. 2020 Aug 07. e12956
    Cellular metabolism dictates T cell effector function in health and disease.
    Shrikant S Kolan, Gaoyang Li, Jonas Aakre Wik, Giulia Malachin, Shuai Guo, Pratibha Kolan, Bjørn Steen Skålhegg.
      In a healthy person, metabolically quiescent T lymphocytes (T cells) circulate between lymph nodes and peripheral tissues in search of antigens. Upon infection, some T cells will encounter cognate antigens followed by proliferation and clonal expansion in a context-dependent manner, to become effector T cells. These events are accompanied by changes in cellular metabolism, known as metabolic reprogramming. The magnitude and variation of metabolic reprogramming are, in addition to antigens, dependent on factors such as nutrients and oxygen to ensure host survival during various diseases. Herein, we describe how metabolic programs define T cell subset identity and effector functions. In addition, we will discuss how metabolic programs can be modulated and affect T cell activity in health and disease using cancer and autoimmunity as examples.
    Keywords:  T cell activation; autoimmunity; cancer; immune cell metabolism
    DOI:  https://doi.org/10.1111/sji.12956
  2. Nat Rev Immunol. 2020 Aug 06.
    Immunometabolism and HIV-1 pathogenesis: food for thought.
    Asier Sáez-Cirión, Irini Sereti.
      Antiretroviral therapies efficiently block HIV-1 replication but need to be maintained for life. Moreover, chronic inflammation is a hallmark of HIV-1 infection that persists despite treatment. There is, therefore, an urgent need to better understand the mechanisms driving HIV-1 pathogenesis and to identify new targets for therapeutic intervention. In the past few years, the decisive role of cellular metabolism in the fate and activity of immune cells has been uncovered, as well as its impact on the outcome of infectious diseases. Emerging evidence suggests that immunometabolism has a key role in HIV-1 pathogenesis. The metabolic pathways of CD4+ T cells and macrophages determine their susceptibility to infection, the persistence of infected cells and the establishment of latency. Immunometabolism also shapes immune responses against HIV-1, and cell metabolic products are key drivers of inflammation during infection. In this Review, we summarize current knowledge of the links between HIV-1 infection and immunometabolism, and we discuss the potential opportunities and challenges for therapeutic interventions.
    DOI:  https://doi.org/10.1038/s41577-020-0381-7
  3. Semin Immunopathol. 2020 Aug 03.
    The interplay between immunosenescence and age-related diseases.
    Florencia Barbé-Tuana, Giselle Funchal, Carine Raquel Richter Schmitz, Rafael Moura Maurmann, Moisés E Bauer.
      The aging immune system (immunosenescence) has been implicated with increased morbidity and mortality in the elderly. Of note, T cell aging and low-grade inflammation (inflammaging) are implicated with several age-related conditions. The expansion of late-differentiated T cells (CD28-), regulatory T cells, increased serum levels of autoantibodies, and pro-inflammatory cytokines were implicated with morbidities during aging. Features of accelerated immunosenescence can be identified in adults with chronic inflammatory conditions, such as rheumatoid arthritis, and are predictive of poor clinical outcomes. Therefore, there is an interplay between immunosenescence and age-related diseases. In this review, we discuss how the aging immune system may contribute to the development and clinical course of age-related diseases such as neurodegenerative diseases, rheumatoid arthritis, cancer, cardiovascular, and metabolic diseases.
    Keywords:  Aging; Cell senescence; Cytokines; Immunosenescence; Inflammaging; T cells
    DOI:  https://doi.org/10.1007/s00281-020-00806-z
  4. Cancers (Basel). 2020 Jul 31. pii: E2134. [Epub ahead of print]12(8):
    Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies.
    Lynda Wyld, Ilaria Bellantuono, Tamara Tchkonia, Jenna Morgan, Olivia Turner, Fiona Foss, Jayan George, Sarah Danson, James L Kirkland.
      Cellular senescence is a key component of human aging that can be induced by a range of stimuli, including DNA damage, cellular stress, telomere shortening, and the activation of oncogenes. Senescence is generally regarded as a tumour suppressive process, both by preventing cancer cell proliferation and suppressing malignant progression from pre-malignant to malignant disease. It may also be a key effector mechanism of many types of anticancer therapies, such as chemotherapy, radiotherapy, and endocrine therapies, both directly and via bioactive molecules released by senescent cells that may stimulate an immune response. However, senescence may contribute to reduced patient resilience to cancer therapies and may provide a pathway for disease recurrence after cancer therapy. A new group of drugs, senotherapies, (drugs which interact with senescent cells to interfere with their pro-aging impacts by either selectively destroying senescent cells (senolytic drugs) or inhibiting their function (senostatic drugs)) are under active investigation to determine whether they can enhance the efficacy of cancer therapies and improve resilience to cancer treatments. Senolytic drugs include quercetin, navitoclax, and fisetin and preclinical and early phase clinical data are emerging of their potential role in cancer treatments, although none are yet in routine use clinically. This article provides a review of these issues.
    Keywords:  aging; cancer; frailty; geriatric oncology; senescence; senolytics; senotherapies
    DOI:  https://doi.org/10.3390/cancers12082134
  5. Iran J Pathol. 2020 ;15(3): 225-231
    Expression Pattern of Telomerase Reverse Transcriptase (hTERT) Variants and Bcl-2 in Peripheral Lymphocytes of Systemic Lupus Erythematosus Patients.
    Armin Attar, Mohsen Khosravi Maharlooei, Mohammad Ali Nazarinia, Ahmad Hosseini, Zohre Bajalli, Yalda Sadat Moeini, Ahmad Monabati, Fatemeh Amirmoezi, Mansooreh Jaberipour, Mojtaba Habibagahi.
       Background & Objective: It is not clear whether activated lymphocytes of patients with systemic lupus erythematosus (SLE) are more proliferative or less apoptotic. We aimed to delineate potential differences between B and T cells of SLE patients compared to healthy controls regarding the telomerase activity and apoptosis status.
    Methods: In this cross-sectional case control study, Blood samples were taken from 10 SLE patients and 10 healthy controls. B and T cells were separated using magnetic cell sorting system. Telomeric repeat amplification protocol (TRAP) assay and real-time PCR were used to determine the telomerase activity and the expression of alternatively spliced variants.
    Results: Four patients under treatment showed significant telomerase activity in their T cells. Four of the newly diagnosed patients showed telomerase activity in their B cells (20% of all patients and 40% of new onset patients). There was no specific pattern of human telomerase reverse transcriptase variant expression within the patients' lymphocytes. A significantly reduced expression of Bcl-2 was detected in B cells (P=0.018) and a trend toward lower Bcl-2 expression in T cells was seen in SLE patients compared to healthy controls.
    Conclusion: Although not definitive, our results may suggest that B cells may have more active roles during the earlier phases of the disease attack, while T cells take over when the disease reaches its chronic stages.
    Keywords:  Apoptosis; Lymphocyte; Systemic Lupus Erythematosus; Telomerase
    DOI:  https://doi.org/10.30699/ijp.2020.110994.2187
  6. Int Immunol. 2020 Aug 07. pii: dxaa051. [Epub ahead of print]
    Multiple developmental pathways lead to the generation of CD4 T cell memory.
    Shintaro Hojyo, Damon Tumes, Akihiko Murata, Koji Tokoyoda.
      Long-term immunological memory mediated by CD4 T cells provides a rapid protection against previously encountered pathogens or antigens. However, it is still controversial how memory CD4 T cells are generated and maintained. Unclear definitions of T cell memory may be partially responsible for this controversy. It is becoming clear that diverse pathways are responsible for the differentiation and long-term persistence of memory T cells. We herein discuss the diversity of memory cell generation, describing a novel population of resting memory CD4 T cells and their precursors.
    Keywords:  Memory T helper cell; antigen; bone marrow; effector; niche
    DOI:  https://doi.org/10.1093/intimm/dxaa051
  7. Aging Cell. 2020 Aug 04. e13208
    Inhibition of Cdc42 activity extends lifespan and decreases circulating inflammatory cytokines in aged female C57BL/6 mice.
    Maria Carolina Florian, Hanna Leins, Michael Gobs, Yang Han, Gina Marka, Karin Soller, Angelika Vollmer, Vadim Sakk, Kalpana J Nattamai, Ahmad Rayes, Xueheng Zhao, Kenneth Setchell, Medhanie Mulaw, Wolfgang Wagner, Yi Zheng, Hartmut Geiger.
      Cdc42 is a small RhoGTPase regulating multiple functions in eukaryotic cells. The activity of Cdc42 is significantly elevated in several tissues of aged mice, while the Cdc42 gain-of-activity mouse model presents with a premature aging-like phenotype and with decreased lifespan. These data suggest a causal connection between elevated activity of Cdc42, aging, and reduced lifespan. Here, we demonstrate that systemic treatment of aged (75-week-old) female C57BL/6 mice with a Cdc42 activity-specific inhibitor (CASIN) for 4 consecutive days significantly extends average and maximum lifespan. Moreover, aged CASIN-treated animals displayed a youthful level of the aging-associated cytokines IL-1β, IL-1α, and INFγ in serum and a significantly younger epigenetic clock as based on DNA methylation levels in blood cells. Overall, our data show that systemic administration of CASIN to reduce Cdc42 activity in aged mice extends murine lifespan.
    Keywords:  Cdc42; aging; epigenetic clock; inflammaging; interferon gamma; lifespan
    DOI:  https://doi.org/10.1111/acel.13208
  8. Nat Metab. 2020 Aug 03.
    Metabolic conditioning of CD8+ effector T cells for adoptive cell therapy.
    Ramon I Klein Geltink, Joy Edwards-Hicks, Petya Apostolova, David O'Sullivan, David E Sanin, Annette E Patterson, Daniel J Puleston, Nina A M Ligthart, Joerg M Buescher, Katarzyna M Grzes, Agnieszka M Kabat, Michal Stanczak, Jonathan D Curtis, Fabian Hässler, Franziska M Uhl, Mario Fabri, Robert Zeiser, Edward J Pearce, Erika L Pearce.
      CD8+ effector T (TE) cell proliferation and cytokine production depends on enhanced glucose metabolism. However, circulating T cells continuously adapt to glucose fluctuations caused by diet and inter-organ metabolite exchange. Here we show that transient glucose restriction (TGR) in activated CD8+ TE cells metabolically primes effector functions and enhances tumour clearance in mice. Tumour-specific TGR CD8+ TE cells co-cultured with tumour spheroids in replete conditions display enhanced effector molecule expression, and adoptive transfer of these cells in a murine lymphoma model leads to greater numbers of immunologically functional circulating donor cells and complete tumour clearance. Mechanistically, TE cells treated with TGR undergo metabolic remodelling that, after glucose re-exposure, supports enhanced glucose uptake, increased carbon allocation to the pentose phosphate pathway (PPP) and a cellular redox shift towards a more reduced state-all indicators of a more anabolic programme to support their enhanced functionality. Thus, metabolic conditioning could be used to promote efficiency of T-cell products for adoptive cellular therapy.
    DOI:  https://doi.org/10.1038/s42255-020-0256-z
  9. Cell Metab. 2020 Jul 22. pii: S1550-4131(20)30359-4. [Epub ahead of print]
    Mitochondrial Oxidative Damage Underlies Regulatory T Cell Defects in Autoimmunity.
    Themis Alissafi, Lydia Kalafati, Maria Lazari, Anastasia Filia, Ismini Kloukina, Maria Manifava, Jong-Hyung Lim, Vasileia Ismini Alexaki, Nicholas T Ktistakis, Triantafyllos Doskas, George A Garinis, Triantafyllos Chavakis, Dimitrios T Boumpas, Panayotis Verginis.
      Regulatory T cells (Tregs) are vital for the maintenance of immune homeostasis, while their dysfunction constitutes a cardinal feature of autoimmunity. Under steady-state conditions, mitochondrial metabolism is critical for Treg function; however, the metabolic adaptations of Tregs during autoimmunity are ill-defined. Herein, we report that elevated mitochondrial oxidative stress and a robust DNA damage response (DDR) associated with cell death occur in Tregs in individuals with autoimmunity. In an experimental autoimmune encephalitis (EAE) mouse model of autoimmunity, we found a Treg dysfunction recapitulating the features of autoimmune Tregs with a prominent mtROS signature. Scavenging of mtROS in Tregs of EAE mice reversed the DDR and prevented Treg death, while attenuating the Th1 and Th17 autoimmune responses. These findings highlight an unrecognized role of mitochondrial oxidative stress in defining Treg fate during autoimmunity, which may facilitate the design of novel immunotherapies for diseases with disturbed immune tolerance.
    Keywords:  DNA damage response; autoimmunity; lysosome; metabolism; mitochondrial oxidative stress; regulatory T cell
    DOI:  https://doi.org/10.1016/j.cmet.2020.07.001
  10. Cell Metab. 2020 Jul 31. pii: S1550-4131(20)30362-4. [Epub ahead of print]
    Memory CD8+ T Cells Balance Pro- and Anti-inflammatory Activity by Reprogramming Cellular Acetate Handling at Sites of Infection.
    Maria L Balmer, Eric H Ma, Andrew Thompson, Raja Epple, Gunhild Unterstab, Jonas Lötscher, Philippe Dehio, Christian M Schürch, Jan D Warncke, Gaëlle Perrin, Anne-Kathrin Woischnig, Jasmin Grählert, Jordan Löliger, Nadine Assmann, Glenn R Bantug, Olivier P Schären, Nina Khanna, Adrian Egli, Lukas Bubendorf, Katharina Rentsch, Siegfried Hapfelmeier, Russell G Jones, Christoph Hess.
      Serum acetate increases upon systemic infection. Acutely, assimilation of acetate expands the capacity of memory CD8+ T cells to produce IFN-γ. Whether acetate modulates memory CD8+ T cell metabolism and function during pathogen re-encounter remains unexplored. Here we show that at sites of infection, high acetate concentrations are being reached, yet memory CD8+ T cells shut down the acetate assimilating enzymes ACSS1 and ACSS2. Acetate, being thus largely excluded from incorporation into cellular metabolic pathways, now had different effects, namely (1) directly activating glutaminase, thereby augmenting glutaminolysis, cellular respiration, and survival, and (2) suppressing TCR-triggered calcium flux, and consequently cell activation and effector cell function. In vivo, high acetate abundance at sites of infection improved pathogen clearance while reducing immunopathology. This indicates that, during different stages of the immune response, the same metabolite-acetate-induces distinct immunometabolic programs within the same cell type.
    Keywords:  acetate; glutaminolysis; immunometabolism; immunopathology; infection; memory CD8+ T cells
    DOI:  https://doi.org/10.1016/j.cmet.2020.07.004
  11. J Transl Autoimmun. 2020 ;3 100046
    Immunometabolism in the pathogenesis of systemic lupus erythematosus.
    Chen-Xing Zhang, Hui-Yu Wang, Lei Yin, You-Ying Mao, Wei Zhou.
      Systemic lupus erythematosus (SLE) is a typical autoimmune disease characterized by chronic inflammation and pathogenic auto-antibodies. Apart from B cells, dysregulation of other immune cells also plays an essential role in the pathogenesis and development of the disease including CD4+T cells, dendritic cells, macrophages and neutrophils. Since metabolic programs control immune cell fate and function, they are critical checkpoints in an effective immune response and are involved in the etiology of autoimmune disease. In addition, mitochondria and oxidative stress are both involved in cellular metabolism and is also essential in immune response. In this review, apart from the disturbed immune system, we will discuss mitochondrial dysfunction, oxidative stress, abnormal metabolism (including glucose, lipid and amino acid metabolism) of immune cells as well as epigenetic control of metabolism reprogramming to elucidate the underlying pathogenic mechanisms of systemic lupus erythematosus.
    Keywords:  Immune response; Metabolic programs; Pathogenesis; Systemic lupus erythematosus (SLE)
    DOI:  https://doi.org/10.1016/j.jtauto.2020.100046
  12. Mol Oncol. 2020 Aug 03.
    Autophagy, the innate immune response and cancer.
    Chelsea Gerada, Kevin M Ryan.
      Autophagy is a cellular degradation and recycling system, which can interact with components of innate immune signalling pathways to enhance pathogen clearance, in both immune and non-immune cells. Whilst this interaction is often beneficial for pathogen clearance, it can have varying outcomes in regards to tumorigenesis. Autophagy and the innate immune response can have both pro- and anti-tumorigenic effects at different stages of tumorigenesis due to the plastic nature of the tumour microenvironment (TME). Although both of these components have been studied in isolation as potential therapeutic targets, there has been less research concerning the interaction between autophagy and the innate immune response within the TME. As the innate immune response is critical for the formation of an effective anti-tumour adaptive immune response, targeting autophagy pathways in both tumour cells and innate immune cells could enhance tumour clearance. Within tumour cells, autophagy pathways are intertwined with pattern recognition receptor (PRR), inflammatory and cell death pathways, and therefore can alter the immunogenicity of the TME and development of the anti-tumour immune response. In innate immune cells, autophagy components can have autophagy-independent roles in functional pathways, and therefore could be valuable targets for enhancing immune cell function in the TME and immunotherapy. This review highlights the individual importance of autophagy and the innate immune response to tumorigenesis, and also explains the complex interactions between these pathways in the TME.
    Keywords:  Autophagy; cancer; immunotherapy; innate immune response; tumor microenvironment
    DOI:  https://doi.org/10.1002/1878-0261.12774
  13. Blood Adv. 2020 Aug 11. 4(15): 3594-3605
    Adenosine monophosphate deaminase 3 null mutation causes reduction of naive T cells in mouse peripheral blood.
    Xiaoming Zhan, Xue Zhong, Jin Huk Choi, Lijing Su, Jianhui Wang, Evan Nair-Gill, Priscilla Anderton, Xiaohong Li, Miao Tang, Jamie Russell, Sara Ludwig, Thomas Gallagher, Bruce Beutler.
      Adenosine monophosphate deaminase 3 (Ampd3) encodes the erythrocyte isoform of the adenosine monophosphate (AMP) deaminase gene family. Mutations in this gene have been reported in humans, leading to autosomal-recessive erythrocyte AMP deaminase deficiency. However, the mutation is considered clinically asymptomatic. Using N-ethyl-N-nitrosourea mutagenesis to find mutations that affect peripheral lymphocyte populations, we identified 5 Ampd3 mutations (Ampd3guangdong, Ampd3carson, Ampd3penasco, Ampd3taos, and Ampd3commanche) that strongly correlated with a reduction in naive CD4+ T and naive CD8+ T-cell populations. Causation was confirmed by targeted ablation of Ampd3. Knockout mice had reduced frequencies of CD62LhiCD44lo CD4+ naive and CD8+ naive T cells. Interestingly, these phenotypes were restricted to T cells circulating in peripheral blood and were not seen in T cells from secondary lymphoid organs (lymph nodes and spleen). We found that reduction of naive T cells in the peripheral blood of Ampd3-/- mice was caused by T-cell-extrinsic factor(s), which we hypothesize to be elevated levels of adenosine triphosphate released by Ampd3-deficient erythrocytes. These findings provide an example in which disruption of an erythrocyte-specific protein can affect the physiological status of lymphocytes in peripheral blood.
    DOI:  https://doi.org/10.1182/bloodadvances.2020001762
  14. Nat Metab. 2020 Aug 03.
    Metabolic communication during exercise.
    Robyn M Murphy, Matthew J Watt, Mark A Febbraio.
      The coordination of nutrient sensing, delivery, uptake and utilization is essential for maintaining cellular, tissue and whole-body homeostasis. Such synchronization can be achieved only if metabolic information is communicated between the cells and tissues of the entire organism. During intense exercise, the metabolic demand of the body can increase approximately 100-fold. Thus, exercise is a physiological state in which intertissue communication is of paramount importance. In this Review, we discuss the physiological processes governing intertissue communication during exercise and the molecules mediating such cross-talk.
    DOI:  https://doi.org/10.1038/s42255-020-0258-x
  15. Front Immunol. 2020 ;11 1474
    Nicotine Changes the microRNA Profile to Regulate the FOXO Memory Program of CD8+ T Cells in Rheumatoid Arthritis.
    Caroline Wasén, Caroline Ospelt, Alessandro Camponeschi, Malin C Erlandsson, Karin M E Andersson, Sofia Töyrä Silfverswärd, Steffen Gay, Maria I Bokarewa.
      Objective: Smoking suppresses PD-1 expression in patients with rheumatoid arthritis (RA). In this study, we assess if smoking changed the epigenetic control over CD8+ T cell memory formation through a microRNA (miR) dependent mechanism. Methods: Phenotypes of CD8+ T cells from smokers and non-smokers, RA and healthy, were analyzed by flow cytometry. A microarray analysis was used to screen for differences in miR expression. Sorted CD8+ cells were in vitro stimulated with nicotine and analyzed for transcription of miRs and genes related to memory programming by qPCR. Results: CD27+CD107a-CD8+ T cells, defining a naïve-memory population, had low expression of PD-1. Additionally, the CD27+ population was more frequent in smokers (p = 0.0089). Smokers were recognized by differential expression of eight miRs. Let-7c-5p, let-7d-5p and let-7e-5p, miR-92a-3p, miR-150-5p, and miR-181-5p were up regulated, while miR-3196 and miR-4723-5p were down regulated. These miRs were predicted to target proteins within the FOXO-signaling pathway involved in CD8+ memory programming. Furthermore, miR-92a-3p was differentially expressed in CD8+ cells with naïve-memory predominance. Nicotine exposure of CD8+ cells induced the expression of miR-150-5p and miR-181a-5p in the naïve-memory cells in vitro. Additionally, nicotine exposure inverted the ratio between mRNAs of proteins in the FOXO pathway and their targeting miRs. Conclusions: Smokers have a high prevalence of CD8+ T cells with a naïve-memory phenotype. These cells express a miR profile that interacts with the memory programming conducted through the FOXO pathway.
    Keywords:  CD8+ T cell; FOXO signaling pathway; memory T cell; microRNA; programmed cell death 1 (PD-1); rheumatoid arthritis
    DOI:  https://doi.org/10.3389/fimmu.2020.01474
  16. Front Immunol. 2020 ;11 1469
    Role of Epigenetic Modifications in Inhibitory Immune Checkpoints in Cancer Development and Progression.
    Reem Saleh, Salman M Toor, Varun Sasidharan Nair, Eyad Elkord.
      A balance between co-inhibitory and co-stimulatory signals in the tumor microenvironment (TME) is critical to suppress tumor development and progression, primarily via maintaining effective immunosurveillance. Aberrant expression of immune checkpoints (ICs), including programmed cell death protein 1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), T cell immunoglobulin and mucin-domain containing-3 (TIM-3), lymphocyte-activation gene 3 (LAG-3) and T cell immunoreceptor with Ig and ITIM domains (TIGIT), can create an immune-subversive environment, which helps tumor cells to evade immune destruction. Recent studies showed that epigenetic modifications play critical roles in regulating the expression of ICs and their ligands in the TME. Reports showed that the promoter regions of genes encoding ICs/IC ligands can undergo inherent epigenetic alterations, such as DNA methylation and histone modifications (acetylation and methylation). These epigenetic aberrations can significantly contribute to the transcriptomic upregulation of ICs and their ligands. Epigenetic therapeutics, including DNA methyltransferase and histone deacetylase inhibitors, can be used to revert these epigenetic anomalies acquired during the progression of disease. These discoveries have established a promising therapeutic modality utilizing the combination of epigenetic and immunotherapeutic agents to restore the physiological epigenetic profile and to re-establish potent host immunosurveillance mechanisms. In this review, we highlight the roles of epigenetic modifications on the upregulation of ICs, focusing on tumor development, and progression. We discuss therapeutic approaches of epigenetic modifiers, including clinical trials in various cancer settings and their impact on current and future anti-cancer therapies.
    Keywords:  DNA methylation; cancer; epigenetics; histone modifications; immune checkpoints; therapeutic targets
    DOI:  https://doi.org/10.3389/fimmu.2020.01469
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