{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T21:43:04Z","timestamp":1793050984020,"version":"4.5.0"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,5,4]],"date-time":"2021-05-04T00:00:00Z","timestamp":1620086400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Immune-checkpoint (IC) inhibitors have revolutionized the treatment of multiple solid tumors and defined lymphomas, but they are largely ineffective in acute myeloid leukemia (AML). The reason why especially PD1\/PD-L1 blocking agents are not efficacious is not well-understood but it may be due to the contribution of different IC ligand\/receptor interactions that determine the function of T cells in AML.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>To analyze the interactions of IC ligands and receptors in AML, we performed a comprehensive transcriptomic analysis of FACS-purified leukemia stem\/progenitor cells and paired bone marrow (BM)-infiltrating CD4<jats:sup>+<\/jats:sup> and CD8<jats:sup>+<\/jats:sup> T cells from 30 patients with AML. The gene expression profiles of activating and inhibiting IC ligands and receptors were correlated with the clinical data. Epigenetic mechanisms were studied by inhibiting the histone deacetylase with valproic acid or by gene silencing of <jats:italic>PAC1<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We observed that IC ligands and receptors were mainly upregulated in leukemia stem cells. The gene expression of activating IC ligands and receptors correlated with improved prognosis and vice versa. In contrast, the majority of IC receptor genes were downregulated in BM-infiltrating CD8<jats:sup>+<\/jats:sup> T cells and partially in CD4<jats:sup>+<\/jats:sup> T cells, due to pathological chromatin remodeling <jats:italic>via<\/jats:italic> histone deacetylation. Therefore, treatment with histone deacetylase inhibitor (HDACi) or silencing of <jats:italic>PAC1<\/jats:italic>, as a T cell-specific epigenetic modulator, significantly increased the expression of IC receptors and defined effector molecules in CD8<jats:sup>+<\/jats:sup> T cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our results suggest that CD8<jats:sup>+<\/jats:sup> T cells in AML are dysfunctional mainly due to pathological epigenetic silencing of activating IC receptors rather than due to signaling by immune inhibitory IC receptors, which may explain the limited efficacy of antibodies that block immune-inhibitory ICs in AML.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fonc.2021.663406","type":"journal-article","created":{"date-parts":[[2021,5,4]],"date-time":"2021-05-04T13:43:24Z","timestamp":1620135804000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":24,"title":["Epigenetic Silencing of Immune-Checkpoint Receptors in Bone Marrow- Infiltrating T Cells in Acute Myeloid Leukemia"],"prefix":"10.3389","volume":"11","author":[{"given":"Ramin","family":"Radpour","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miriam","family":"Stucki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carsten","family":"Riether","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrian F.","family":"Ochsenbein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,5,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2014.89","article-title":"Regulation of hematopoietic and leukemic stem cells by the immune system","volume":"22","author":"Riether","year":"2015","journal-title":"Cell Death Differ"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/ni1080","article-title":"Acute myeloid leukemia originates from a hierarchy of leukemic stem cell classes that differ in self-renewal capacity","volume":"5","author":"Hope","year":"2004","journal-title":"Nat Immunol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2017.169516","article-title":"Memory CD8(+) T cells support the maintenance of hematopoietic stem cells in the bone marrow","volume":"103","author":"Geerman","year":"2018","journal-title":"Haematologica"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2009.05.046","article-title":"CD47 is upregulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis","volume":"138","author":"Jaiswal","year":"2009","journal-title":"Cell"},{"key":"B5","doi-asserted-by":"publisher","first-page":"280sr1","DOI":"10.1126\/scitranslmed.3010274","article-title":"On being less tolerant: enhanced cancer immunosurveillance enabled by targeting checkpoints and agonists of T cell activation","volume":"7","author":"Lesokhin","year":"2015","journal-title":"Sci Transl Med"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2020.569017","article-title":"Molecular Immunotherapy: Promising Approach to Treat Metastatic Colorectal Cancer by Targeting Resistant Cancer Cells or Cancer Stem Cells","volume":"10","author":"Forster","year":"2020","journal-title":"Front Oncol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3239","article-title":"The blockade of immune checkpoints in cancer immunotherapy","volume":"12","author":"Pardoll","year":"2012","journal-title":"Nat Rev Cancer"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1172\/jci129204","article-title":"Immune escape and immunotherapy of acute myeloid leukemia","volume":"130","author":"Vago","year":"2020","journal-title":"J Clin Invest"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2019000792","article-title":"Immune profiles in acute myeloid leukemia bone marrow associate with patient age, T-cell receptor clonality, and survival","volume":"4","author":"Br\u00fcck","year":"2020","journal-title":"Blood Adv"},{"key":"B10","doi-asserted-by":"publisher","first-page":"380","DOI":"10.1016\/j.ccell.2020.06.002","article-title":"Immunogenomic Landscape of Hematological Malignancies","volume":"38","author":"Dufva","year":"2020","journal-title":"Cancer Cell"},{"key":"B11","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1007\/s11912-019-0781-7","article-title":"Immune Checkpoint Inhibitors in Acute Myeloid Leukemia: Novel Combinations and Therapeutic Targets","volume":"21","author":"Stahl","year":"2019","journal-title":"Curr Oncol Rep"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/s41375-019-0441-9","article-title":"CD8(+) T cells expand stem and progenitor cells in favorable but not adverse risk acute myeloid leukemia","volume":"33","author":"Radpour","year":"2019","journal-title":"Leukemia"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-019-0577-9","article-title":"The phosphatase PAC1 acts as a T cell suppressor and attenuates host antitumor immunity","volume":"21","author":"Dan","year":"2020","journal-title":"Nat Immunol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.20892\/j.issn.2095-3941.2020.0338","article-title":"Exhausted T cells and epigenetic status","volume":"17","author":"Zeng","year":"2020","journal-title":"Cancer Biol Med"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2020.554570","article-title":"Epigenetic Alterations and Biomarkers for Immune Checkpoint Inhibitors-Current Standards and Future Perspectives in Malignant Pleural Mesothelioma Treatment","volume":"10","author":"Yoshikawa","year":"2020","journal-title":"Front Oncol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.1542","article-title":"Alterations of immune response of Non-Small Cell Lung Cancer with Azacytidine","volume":"4","author":"Wrangle","year":"2013","journal-title":"Oncotarget"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2013.355","article-title":"Expression of PD-L1, PD-L2, PD-1 and CTLA4 in myelodysplastic syndromes is enhanced by treatment with hypomethylating agents","volume":"28","author":"Yang","year":"2014","journal-title":"Leukemia"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.Cd-18-0774","article-title":"Efficacy, Safety, and Biomarkers of Response to Azacitidine and Nivolumab in Relapsed\/Refractory Acute Myeloid Leukemia: A Nonrandomized, Open-Label, Phase II Study","volume":"9","author":"Daver","year":"2019","journal-title":"Cancer Discov"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-03-206672","article-title":"PD-1\/PD-L1 interactions inhibit antitumor immune responses in a murine acute myeloid leukemia model","volume":"114","author":"Zhang","year":"2009","journal-title":"Blood"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2015.26","article-title":"Blocking programmed cell death 1 in combination with adoptive cytotoxic T-cell transfer eradicates chronic myelogenous leukemia stem cells","volume":"29","author":"Riether","year":"2015","journal-title":"Leukemia"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2008-09-179697","article-title":"Programmed death 1 signaling on chronic myeloid leukemia-specific T cells results in T-cell exhaustion and disease progression","volume":"114","author":"Mumprecht","year":"2009","journal-title":"Blood"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2018-05-849802","article-title":"Bifunctional PD-1 x alphaCD3 x alphaCD33 fusion protein reverses adaptive immune escape in acute myeloid leukemia","volume":"132","author":"Herrmann","year":"2018","journal-title":"Blood"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.31896","article-title":"The distribution of T-cell subsets and the expression of immune checkpoint receptors and ligands in patients with newly diagnosed and relapsed acute myeloid leukemia","volume":"125","author":"Williams","year":"2019","journal-title":"Cancer"},{"key":"B24","article-title":"Hematopoietic stem cells: interplay with immunity","volume":"2","author":"Zhang","year":"2012","journal-title":"Am J Blood Res"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2002-06-1668","article-title":"CTLA-4 is not restricted to the lymphoid cell lineage and can function as a target molecule for apoptosis induction of leukemic cells","volume":"101","author":"Pistillo","year":"2003","journal-title":"Blood"},{"key":"B26","doi-asserted-by":"publisher","first-page":"298ra119","DOI":"10.1126\/scitranslmed.aab1740","article-title":"Tyrosine kinase inhibitor-induced CD70 expression mediates drug resistance in leukemia stem cells by activating Wnt signaling","volume":"7","author":"Riether","year":"2015","journal-title":"Sci Transl Med"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-08-2650","article-title":"Glucocorticoid-induced tumor necrosis factor receptor-related protein ligand subverts immunosurveillance of acute myeloid leukemia in humans","volume":"69","author":"Baessler","year":"2009","journal-title":"Cancer Res"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2015.07.011","article-title":"A TIM-3\/Gal-9 Autocrine Stimulatory Loop Drives Self-Renewal of Human Myeloid Leukemia Stem Cells and Leukemic Progression","volume":"17","author":"Kikushige","year":"2015","journal-title":"Cell Stem Cell"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1007\/978-981-15-3266-5_9","article-title":"Functions of Immune Checkpoint Molecules Beyond Immune Evasion","volume":"1248","author":"Zhang","year":"2020","journal-title":"Adv Exp Med Biol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1038\/s41422-020-0343-4","article-title":"Immune checkpoint signaling and cancer immunotherapy","volume":"30","author":"He","year":"2020","journal-title":"Cell Res"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.01469","article-title":"Role of Epigenetic Modifications in Inhibitory Immune Checkpoints in Cancer Development and Progression","volume":"11","author":"Saleh","year":"2020","journal-title":"Front Immunol"},{"key":"B32","doi-asserted-by":"publisher","first-page":"184","DOI":"10.18632\/genesandcancer.65","article-title":"Histone acetyltransferases and histone deacetylases in B- and T-cell development, physiology and malignancy","volume":"6","author":"Haery","year":"2015","journal-title":"Genes Cancer"},{"key":"B33","doi-asserted-by":"publisher","first-page":"695","DOI":"10.1038\/ni.3456","article-title":"Tcf1 and Lef1 transcription factors establish CD8(+) T cell identity through intrinsic HDAC activity","volume":"17","author":"Xing","year":"2016","journal-title":"Nat Immunol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1038\/s41375-018-0062-8","article-title":"Histone deacetylase (HDAC) inhibitor ACY241 enhances anti-tumor activities of antigen-specific central memory cytotoxic T lymphocytes against multiple myeloma and solid tumors","volume":"32","author":"Bae","year":"2018","journal-title":"Leukemia"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.7150\/jca.34471","article-title":"Histone deacetylase inhibition up-regulates MHC class I to facilitate cytotoxic T lymphocyte-mediated tumor cell killing in glioma cells","volume":"10","author":"Sun","year":"2019","journal-title":"J Cancer"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2020.00699","article-title":"Inhibition of Histone Deacetylase (HDAC) Enhances Checkpoint Blockade Efficacy by Rendering Bladder Cancer Cells Visible for T Cell-Mediated Destruction","volume":"10","author":"Burke","year":"2020","journal-title":"Front Oncol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2020.576391","article-title":"Recent Update of HDAC Inhibitors in Lymphoma","volume":"8","author":"Chen","year":"2020","journal-title":"Front Cell Dev Biol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.7150\/jca.44622","article-title":"HDAC Inhibitor, CG-745, Enhances the Anti-Cancer Effect of Anti-PD-1 Immune Checkpoint Inhibitor by Modulation of the Immune Microenvironment","volume":"11","author":"Kim","year":"2020","journal-title":"J Cancer"},{"key":"B39","doi-asserted-by":"publisher","first-page":"e001696","DOI":"10.1136\/jitc-2020-001696","article-title":"Frequent amplification of HDAC genes and efficacy of HDAC inhibitor chidamide and PD-1 blockade combination in soft tissue sarcoma","volume":"9","author":"Que","year":"2021","journal-title":"J Immunother Cancer"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2019.11.155","article-title":"Blockade of myeloid-derived suppressor cell function by valproic acid enhanced anti-PD-L1 tumor immunotherapy","volume":"522","author":"Adeshakin","year":"2020","journal-title":"Biochem Biophys Res Commun"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2021.663406\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,5,4]],"date-time":"2021-05-04T13:43:27Z","timestamp":1620135807000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2021.663406\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,4]]},"references-count":40,"alternative-id":["10.3389\/fonc.2021.663406"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2021.663406","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,4]]},"article-number":"663406"}}