The use of immunotherapy to treat patients with myelodysplastic syndromes (MDS) shows promise but is limited by our incomplete understanding of the immunologic milieu. In solid tumors, CD141Hi conventional dendritic cells (CD141Hi cDCs) are necessary for antitumor immunosurveillance and the response to immunotherapy. Here, we found that CD141Hi cDCs are reduced in MDS bone marrow and based on the premise established in solid tumors, we hypothesized that reduced numbers of CD141Hi cDCs are associated with inferior overall survival in MDS patients. We found that MDS patients with reduced numbers of CD141Hi cDCs, but not other DC populations, showed reduced overall survival. To examine the basis for reduction in CD141Hi cDCs, we found fewer numbers of progenitors committed to DC differentiation in the MDS bone marrow and these progenitors expressed lower levels of interferon regulatory factor-8 (IRF8), a master regulator of CD141Hi cDC differentiation. To rescue impaired CD141Hi cDC differentiation, we used pharmacologic inhibition of lysine-specific demethylase 1A (LSD1) to promote CD141Hi cDC differentiation by MDS progenitors. These data reveal a previously unrecognized element of the MDS immunologic milieu. Epigenetic regulation of CD141Hi cDC differentiation offers an intriguing opportunity for intervention and a potential adjunct to immunotherapy for patients with MDS.
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Ma X, Does M, Raza A, Mayne ST. Myelodysplastic syndromes: incidence and survival in the United States. Cancer. 2007;109:1536–42.
Nachtkamp K, Stark R, Strupp C, Kündgen A, Giagounidis A, Aul C, et al. Causes of death in 2877 patients with myelodysplastic syndromes. Ann Hematol. 2016;95:937–44.
Nieto M, Demolis P, Béhanzin E, Moreau A, Hudson I, Flores B, et al. The European medicines agency review of decitabine (Dacogen) for the treatment of adult patients with acute myeloid leukemia: summary of the scientific assessment of the committee for medicinal products for human use. Oncologist. 2016;21:692–700.
Jabbour E, Garcia-Manero G, Batty N, Shan J, O’Brien S, Cortes J, et al. Outcome of patients with myelodysplastic syndrome after failure of decitabine therapy. Cancer. 2010;116:3830–4.
Daver N, Garcia-Manero G, Basu S, Boddu PC, Alfayez M, Cortes JE, et al. Efficacy, Safety, and biomarkers of response to azacitidine and nivolumab in relapsed/refractory acute myeloid leukemia: a nonrandomized, open-label, phase II study. Cancer Disco. 2018;9:1–15.
Griffiths EA, Srivastava P, Matsuzaki J, Brumberger Z, Wang ES, Kocent J, et al. NY-ESO-1 vaccination in combination with decitabine induces antigen-specific t-lymphocyte responses in patients with myelodysplastic syndrome. Clin Cancer Res. 2018;24:1019–29.
Wculek SK, Cueto FJ, Mujal AM, Melero I, Krummel MF, Sancho D. Dendritic cells in cancer immunology and immunotherapy. Nat Rev Immunol. 2019;144:646–18.
Broz ML, Binnewies M, Boldajipour B, Nelson AE, Pollack JL, Erle DJ, et al. Dissecting the tumor myeloid compartment reveals rare activating antigen-presenting cells critical for T cell immunity. Cancer Cell. 2014;26:638–52.
Roberts EW, Broz ML, Binnewies M, Headley MB, Nelson AE, Wolf DM, et al. Critical role for CD103(+)/CD141(+) dendritic cells bearing CCR7 for Tumor antigen trafficking and priming of T cell immunity in melanoma. Cancer Cell. 2016;30:324–36.
Barry KC, Hsu J, Broz ML, Cueto FJ, Binnewies M, Combes AJ, et al. A natural killer–dendritic cell axis defines checkpoint therapy–responsive tumor microenvironments. Nat Med. 2018;24:1–21.
Guilliams M, Ginhoux F, Jakubzick C, Naik SH, Onai N, Schraml BU, et al. Dendritic cells, monocytes and macrophages: a unified nomenclature based on ontogeny. Nat Rev Immunol. 2014;14:571–8.
Hildner K, Edelson BT, Purtha WE, Diamond M, Matsushita H, Kohyama M, et al. Batf3 deficiency reveals a critical role for CD8alpha+ dendritic cells in cytotoxic T cell immunity. Science. 2008;322:1097–100.
Ruffell B, Chang-Strachan D, Chan V, Rosenbusch A, Ho CMT, Pryer N, et al. Macrophage IL-10 blocks CD8+ T cell-dependent responses to chemotherapy by suppressing IL-12 expression in intratumoral dendritic cells. Cancer Cell. 2014;26:623–37.
Mittal D, Vijayan D, Putz EM, Aguilera AR, Markey KA, Straube J, et al. Interleukin-12 from CD103+ Batf3-dependent dendritic cells required for NK-Cell suppression of metastasis. Cancer Immunol Res. 2017;5:1098–108.
Sánchez-Paulete AR, Cueto FJ, Martínez-López M, Labiano S, Morales-Kastresana A, Rodríguez-Ruiz ME, et al. Cancer Immunotherapy with immunomodulatory anti-CD137 and anti-PD-1 monoclonal antibodies requires BATF3-dependent dendritic cells. Cancer Disco. 2016;6:71–9.
Salmon H, Idoyaga J, Rahman A, Leboeuf M, Remark R, Jordan S, et al. Expansion and activation of CD103(+) dendritic cell progenitors at the tumor site enhances tumor responses to therapeutic PD-L1 and BRAF inhibition. Immunity. 2016;44:924–38.
Spranger S, Dai D, Horton B, Gajewski TF. Tumor-residing Batf3 dendritic cells are required for effector T cell trafficking and adoptive T cell therapy. Cancer Cell. 2017;31:711–4.
Kerkhoff N, Bontkes HJ, Westers TM, de Gruijl TD, Kordasti S, van de Loosdrecht AA. Dendritic cells in myelodysplastic syndromes: from pathogenesis to immunotherapy. Immunotherapy. 2013;5:621–37.
Grambsch PM, Therneau TM. Proportional hazards tests and diagnostics based on weighted residuals. Biometrika. 1994;81:515–26.
Greenberg PL, Tuechler H, Schanz J, Sanz G, Garcia-Manero G, Solé F, et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood. 2012;120:2454–65.
Epling-Burnette PK, Bai F, Painter JS, Rollison DE, Salih HR, Krusch M, et al. Reduced natural killer (NK) function associated with high-risk myelodysplastic syndrome (MDS) and reduced expression of activating NK receptors. Blood. 2007;109:4816–24.
Hémont C, Neel A, Heslan M, Braudeau C, Josien R. Human blood mDC subsets exhibit distinct TLR repertoire and responsiveness. J Leukoc Biol. 2013;93:599–609.
Chiang M-C, Tullett KM, Lee YS, Idris A, Ding Y, McDonald KJ, et al. Differential uptake and cross-presentation of soluble and necrotic cell antigen by human DC subsets. Eur J Immunol. 2016;46:329–39.
Thompson JE, Conlon JP, Yang X, Sanchez PV, Carroll M. Enhanced growth of myelodysplastic colonies in hypoxic conditions. Exp Hematol. 2007;35:21–31.
Lee J, Zhou YJ, Ma W, Zhang W, Aljoufi A, Luh T, et al. Lineage specification of human dendritic cells is marked by IRF8 expression in hematopoietic stem cells and multipotent progenitors. Nat Immunol. 2017;18:877–88.
Sichien D, Scott CL, Martens L, Vanderkerken M, Van Gassen S, Plantinga M, et al. IRF8 transcription factor controls survival and function of terminally differentiated conventional and plasmacytoid dendritic cells, respectively. Immunity. 2016;45:626–40.
Grajales-Reyes GE, Iwata A, Albring J, Wu X, Tussiwand R, Kc W, et al. Batf3 maintains autoactivation of Irf8 for commitment of a CD8α(+) conventional DC clonogenic progenitor. Nat Immunol. 2015;16:708–17.
Schmidt M, Nagel S, Proba J, Thiede C, Ritter M, Waring JF, et al. Lack of interferon consensus sequence binding protein (ICSBP) transcripts in human myeloid leukemias. Blood. 1998;91:22–9.
Waight JD, Banik D, Griffiths EA, Nemeth MJ, Abrams SI. Regulation of the interferon regulatory factor-8 (IRF-8) tumor suppressor gene by the signal transducer and activator of transcription 5 (STAT5) transcription factor in chronic myeloid leukemia. J Biol Chem. 2014;289:15642–52.
Will B, Vogler TO, Narayanagari S, Bartholdy B, Todorova TI, da Silva Ferreira M, et al. Minimal PU.1 reduction induces a preleukemic state and promotes development of acute myeloid leukemia. Nat Med. 2015;21:1172–81.
Gaillard C, Surianarayanan S, Bentley T, Warr MR, Fitch B, Geng H, et al. Identification of IRF8 as a potent tumor suppressor in murine acute promyelocytic leukemia. Blood Adv. 2018;2:2462–6.
Schenk T, Chen WC, Göllner S, Howell L, Jin L, Hebestreit K, et al. Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia. Nat Med. 2012;18:605–11.
Harris WJ, Huang X, Lynch JT, Spencer GJ, Hitchin JR, Li Y, et al. The histone demethylase KDM1A sustains the oncogenic potential of MLL-AF9 leukemia stem cells. Cancer Cell. 2012;21:473–87.
Maes T, Mascaró C, Tirapu I, Estiarte A, Ciceri F, Lunardi S, et al. ORY-1001, a potent and selective covalent KDM1A inhibitor, for the treatment of acute leukemia. Cancer Cell. 2018;33:495–511.
Cusan M, Cai SF, Mohammad HP, Krivtsov A, Chramiec A, Loizou E, et al. LSD1 inhibition exerts its antileukemic effect by recommissioning PU.1- and C/EBPα-dependent enhancers in AML. Blood. 2018;131:1730–42.
Olsson A, Venkatasubramanian M, Chaudhri VK, Aronow BJ, Salomonis N, Singh H, et al. Single-cell analysis of mixed-lineage states leading to a binary cell fate choice. Nature. 2016;537:698–702.
Maiques-Diaz A, Spencer GJ, Lynch JT, Ciceri F, Williams EL, Amaral FMR, et al. Enhancer activation by pharmacologic displacement of LSD1 from GFI1 induces differentiation in acute myeloid leukemia. Cell Rep. 2018;22:3641–59.
Barth J, Abou-El-Ardat K, Dalic D, Kurrle N, Maier A-M, Mohr S, et al. LSD1 inhibition by tranylcypromine derivatives interferes with GFI1-mediated repression of PU.1 target genes and induces differentiation in AML. Leukemia. 2019;33:1411–26.
Bell CC, Fennell KA, Chan Y-C, Rambow F, Yeung MM, Vassiliadis D, et al. Targeting enhancer switching overcomes non-genetic drug resistance in acute myeloid leukaemia. Nat Comm. 2019;10:2723.
Lee J, Breton G, Aljoufi A, Zhou YJ, Puhr S, Nussenzweig MC, et al. Clonal analysis of human dendritic cell progenitor using a stromal cell culture. J Immunol Methods. 2015;425:21–6.
Rouault-Pierre K, Mian SA, Goulard M, Abarrategi A, Di Tulio A, Smith AE, et al. Preclinical modeling of myelodysplastic syndromes. Leukemia. 2017;31:2702–8.
Mohammad HP, Smitheman KN, Kamat CD, Soong D, Federowicz KE, Van Aller GS, et al. A DNA hypomethylation signature predicts antitumor activity of LSD1 inhibitors in SCLC. Cancer Cell. 2015;28:57–69.
Jongbloed SL, Kassianos AJ, McDonald KJ, Clark GJ, Ju X, Angel CE, et al. Human CD141+ (BDCA-3)+ dendritic cells (DCs) represent a unique myeloid DC subset that cross-presents necrotic cell antigens. J Exp Med. 2010;207:1247–60.
Duy C, Teater M, Garrett-Bakelman FE, Lee TC, Meydan C, Glass JL, et al. Rational targeting of cooperating layers of the epigenome yields enhanced therapeutic efficacy against AML. Cancer Discov. 2019;9:872–89.
Kurotaki D, Kawase W, Sasaki H, Nakabayashi J, Nishiyama A, Morse HC, et al. Epigenetic control of early dendritic cell lineage specification by the transcription factor IRF8 in mice. Blood. 2019;133:1803–13.
Ganan-Gomez I, Wei Y, Starczynowski DT, Colla S, Yang H, Cabrero-Calvo M, et al. Deregulation of innate immune and inflammatory signaling in MDS. Leukemia. 2015;29:1458–69.
Kordasti SY, Ingram W, Hayden J, Darling D, Barber L, Afzali B, et al. CD4+CD25high Foxp3+ regulatory T cells in myelodysplastic syndrome (MDS). Blood. 2007;110:847–50.
Chen X, Eksioglu EA, Zhou J, Zhang L, Djeu J, Fortenbery N, et al. Induction of myelodysplasia by myeloid-derived suppressor cells. J Clin Invest. 2013;123:4595–611.
Saft L, Björklund E, Berg E, Hellström-Lindberg E, Porwit A. Bone marrow dendritic cells are reduced in patients with high-risk myelodysplastic syndromes. Leuk Res. 2013;37:266–73.
Kline DE, MacNabb BW, Chen X, Chan W-C, Fosco D, Kline J. CD8α+ dendritic cells dictate leukemia-specific CD8+ T cell fates. J Immunol. 2018;201:3759–69.
Scott CL, Soen B, Martens L, Skrypek N, Saelens W, Taminau J, et al. The transcription factor Zeb2 regulates development of conventional and plasmacytoid DCs by repressing Id2. J Exp Med. 2016;213:897–911.
Liu Y, Bewersdorf JP, Stahl M, Zeidan AM. Immunotherapy in acute myeloid leukemia and myelodysplastic syndromes: the dawn of a new era? Blood Rev. 2019;34:67–83.
Sheng W, LaFleur MW, Nguyen TH, Chen S, Chakravarthy A, Conway JR, et al. LSD1 ablation stimulates anti-tumor immunity and enables checkpoint blockade. Cell. 2018;174:549–63.
First, we thank our patients and their families. We acknowledge the contributions of the Hematologic Procurement Resource at Roswell Park: Laurie Ann Ford, Tara Cronin, Linda G. Lutgen-Dunckley, Brandon L. Martens, and Joseph R. Moberg. We thank Philip L. McCarthy, George L. Chen, Maureen Ross, Barbara J. Bambach, Stephen Schinnagel, and Mary Bayers-Thering for sourcing de-identified healthy donor specimens. We thank our research coordinators Krista Belko and Justin Kocent. We thank Renae Holtz for assistance with shRNA studies and Scott Portwood and Eunice S. Wang for assistance with hypoxia studies. We thank Kelvin Lee for KG-1 cells. We acknowledge Tim Somervaille for helpful discussions. We thank David Eifrig and Charles Flippen for editorial assistance. This work was funded by the Roswell Park Alliance Foundation (EAG and MJN), the Rapaport Foundation (EAG and MJN), NIH grant 5T32 CA085183-17 (SLT), and NIH grant R01 CA172105 (SIA). This work was supported by National Cancer Institute (NCI) grant P30CA016056 involving the use of Roswell Park Flow and Image Cytometry, Bioinformatics, Biostatistics, Laboratory Animal, and Genomics Shared Resources.
Conflict of interest
EAG: Advisory Board/Honoraria: Celgene (Relevant), Boston Scientific, Persimmune, New Link Genetics, Astex/Otsuka (Relevant), Partner Therapeutics, Inc., Alexion Pharmaceuticals, Abbvie, Novartis. Research Funding/Clinical Trials: Astex Pharmaceuticals (clinical trial PI), Celgene (clinical trial PI, research funding), Genentech (research funding), Appelis pharmaceuticals (clinical trial PI). MJN: Genentech (research funding).
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Srivastava, P., Tzetzo, S.L., Gomez, E.C. et al. Inhibition of LSD1 in MDS progenitors restores differentiation of CD141Hi conventional dendritic cells. Leukemia 34, 2460–2472 (2020). https://doi.org/10.1038/s41375-020-0765-5