Wherry, E. J. & Kurachi, M. Molecular and cellular insights into T cell exhaustion. Nat. Rev. Immunol. 15, 486–499 (2015).
Thommen, D. S. & Schumacher, T. N. T Cell dysfunction in cancer. Cancer Cell 33, 547–562 (2018).
Mognol, G. P. et al. Exhaustion-associated regulatory regions in CD8+ tumor-infiltrating T cells. Proc. Natl Acad. Sci. USA 114, E2776–E2785 (2017).
Crawford, A. et al. Molecular and transcriptional basis of CD4+ T cell dysfunction during chronic infection. Immunity 40, 289–302 (2014).
Sen, D. R. et al. The epigenetic landscape of T cell exhaustion. Science 354, 1165–1169 (2016).
Wherry, E. J. et al. Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity 27, 670–684 (2007).
Pauken, K. E. et al. Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade. Science 354, 1160–1165 (2016).
Ghoneim, H. E. et al. De novo epigenetic programs inhibit PD-1 blockade-mediated T cell rejuvenation. Cell 170, 142–157.e19 (2017).
Blackburn, S. D., Shin, H., Freeman, G. J. & Wherry, E. J. Selective expansion of a subset of exhausted CD8 T cells by αPD-L1 blockade. Proc. Natl Acad. Sci. USA 105, 15016–15021 (2008).
Topper, M. J. et al. Epigenetic therapy ties MYC depletion to reversing immune evasion and treating lung cancer. Cell 171, 1284–1300.e21 (2017).
Li, X. et al. Increased IFNγ+ T cells are responsible for the clinical responses of low-dose DNA-demethylating agent decitabine antitumor therapy. Clin. Cancer Res. 23, 6031–6043 (2017).
Topper, M. J., Vaz, M., Marrone, K. A., Brahmer, J. R. & Baylin, S. B. The emerging role of epigenetic therapeutics in immuno-oncology. Nat. Rev. Clin. Oncol. https://doi.org/10.1038/s41571-019-0266-5 (2019).
Aspeslagh, S., Morel, D., Soria, J. C. & Postel-Vinay, S. Epigenetic modifiers as new immunomodulatory therapies in solid tumours. Ann. Oncol. 29, 812–824 (2018).
Tien, F. M., Lu, H. H., Lin, S. Y. & Tsai, H. C. Epigenetic remodeling of the immune landscape in cancer: therapeutic hurdles and opportunities. J. Biomed. Sci. 30, 3 (2023).
Abdel-Hakeem, M. S. et al. Epigenetic scarring of exhausted T cells hinders memory differentiation upon eliminating chronic antigenic stimulation. Nat. Immunol. 22, 1008–1019 (2021).
Almeida, J. R. et al. Superior control of HIV-1 replication by CD8+ T cells is reflected by their avidity, polyfunctionality, and clonal turnover. J. Exp. Med. 204, 2473–2485 (2007).
Chiu, Y. L. et al. Sprouty-2 regulates HIV-specific T cell polyfunctionality. J. Clin. Invest. 124, 198–208 (2014).
Ding, Z. C. et al. Polyfunctional CD4+ T cells are essential for eradicating advanced B-cell lymphoma after chemotherapy. Blood 120, 2229–2239 (2012).
Weng, R. R. et al. Epigenetic modulation of immune synaptic-cytoskeletal networks potentiates γδ T cell-mediated cytotoxicity in lung cancer. Nat. Commun. 12, 2163 (2021).
Li, X. et al. Decitabine priming increases anti-PD-1 antitumor efficacy by promoting CD8+ progenitor exhausted T cell expansion in tumor models. J. Clin. Invest. 133, e165673 (2023).
Kagoya, Y. et al. BET bromodomain inhibition enhances T cell persistence and function in adoptive immunotherapy models. J. Clin. Invest. 126, 3479–3494 (2016).
Kong, W. et al. BET bromodomain protein inhibition reverses chimeric antigen receptor extinction and reinvigorates exhausted T cells in chronic lymphocytic leukemia. J. Clin. Invest. 131, e145459 (2021).
Zhu, H. et al. BET bromodomain inhibition promotes anti-tumor immunity by suppressing PD-L1 expression. Cell Rep. 16, 2829–2837 (2016).
Chee, J. et al. Impaired T cell proliferation by ex vivo BET-inhibition impedes adoptive immunotherapy in a murine melanoma model. Epigenetics 15, 134–144 (2020).
Georgiev, P. et al. BET bromodomain inhibition suppresses human T cell function. Immunohorizons 3, 294–305 (2019).
Gibbons, H. R. et al. Bromodomain inhibitor JQ1 reversibly blocks IFN-γ production. Sci. Rep. 9, 10280 (2019).
Huang, Z. Y. et al. Single-cell analysis of diverse immune phenotypes in malignant pleural effusion. Nat. Commun. 12, 6690 (2021).
Principe, N. et al. Malignant pleural effusions—a window into local anti-tumor T cell immunity? Front. Oncol. 11, 672747 (2021).
Buggert, M. et al. T-bet and Eomes are differentially linked to the exhausted phenotype of CD8+ T cells in HIV infection. PLoS Pathog. 10, e1004251 (2014).
Paley, M. A. et al. Progenitor and terminal subsets of CD8+ T cells cooperate to contain chronic viral infection. Science 338, 1220–1225 (2012).
Ananieva, E. A., Powell, J. D. & Hutson, S. M. Leucine metabolism in T cell activation: mTOR signaling and beyond. Adv. Nutr. 7, 798S–805S (2016).
Ma, C. et al. Upregulated ethanolamine phospholipid synthesis via selenoprotein I is required for effective metabolic reprogramming during T cell activation. Mol. Metab. 47, 101170 (2021).
Aibar, S. et al. SCENIC: single-cell regulatory network inference and clustering. Nat. Methods 14, 1083–1086 (2017).
Filippakopoulos, P. et al. Selective inhibition of BET bromodomains. Nature 468, 1067–1073 (2010).
Philip, M. et al. Chromatin states define tumour-specific T cell dysfunction and reprogramming. Nature 545, 452–456 (2017).
Shi, J. et al. Potent activity of the bromodomain inhibitor OTX015 in multiple myeloma. Mol. Pharm. 15, 4139–4147 (2018).
Henssen, A. et al. Targeting MYCN-driven transcription by BET-bromodomain inhibition. Clin. Cancer Res. 22, 2470–2481 (2016).
Postel-Vinay, S. et al. First-in-human phase I study of the bromodomain and extraterminal motif inhibitor BAY 1238097: emerging pharmacokinetic/pharmacodynamic relationship and early termination due to unexpected toxicity. Eur. J. Cancer 109, 103–110 (2019).
Amorim, S. et al. Bromodomain inhibitor OTX015 in patients with lymphoma or multiple myeloma: a dose-escalation, open-label, pharmacokinetic, phase 1 study. Lancet Haematol. 3, e196–e204 (2016).
Bandopadhayay, P. et al. BET bromodomain inhibition of MYC-amplified medulloblastoma. Clin. Cancer Res. 20, 912–925 (2014).
Shu, S. et al. Response and resistance to BET bromodomain inhibitors in triple-negative breast cancer. Nature 529, 413–417 (2016).
Mertz, J. A. et al. Targeting MYC dependence in cancer by inhibiting BET bromodomains. Proc. Natl Acad. Sci. USA 108, 16669–16674 (2011).
Delmore, J. E. et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell 146, 904–917 (2011).
Wu, R. et al. De novo synthesis and salvage pathway coordinately regulate polyamine homeostasis and determine T cell proliferation and function. Sci. Adv. 6, eabc4275 (2020).
Elmarsafawi, A. G. et al. Modulating the polyamine/hypusine axis controls generation of CD8+ tissue-resident memory T cells. JCI Insight 8, e169308 (2023).
Puleston, D. J. et al. Polyamine metabolism is a central determinant of helper T cell lineage fidelity. Cell 184, 4186–4202.e20 (2021).
O’Brien, K. L. et al. De novo polyamine synthesis supports metabolic and functional responses in activated murine NK cells. Eur. J. Immunol. 51, 91–102 (2021).
Senekowitsch, S. et al. High-dose spermidine supplementation does not increase spermidine levels in blood plasma and saliva of healthy adults: a randomized placebo-controlled pharmacokinetic and metabolomic study. Nutrients 15, 1852 (2023).
Keohane, P. et al. Supplementation of spermidine at 40 mg/day has minimal effects on circulating polyamines: an exploratory double-blind randomized controlled trial in older men. Nutr. Res. 132, 1–14 (2024).
Corces, M. R. et al. An improved ATAC-seq protocol reduces background and enables interrogation of frozen tissues. Nat. Methods 14, 959–962 (2017).


















Leave a Reply