Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells

Journal article


Publication Details

Author(s): Mathew NR, Baumgartner F, Braun L, O'Sullivan D, Thomas S, Waterhouse M, Mueller TA, Hanke K, Taromi S, Apostolova P, Illert AL, Melchinger W, Duquesne S, Schmitt-Graeff A, Osswald L, Yan KL, Weber A, Tugues S, Spath S, Pfeifer D, Follo M, Claus R, Luebbert M, Rummelt C, Bertz H, Waesch R, Haag J, Schmidts A, Schultheiss M, Bettinger D, Thimme R, Ullrich E, Tanriver Y, Vuong GL, Arnold R, Hemmati P, Wolf D, Ditschkowski M, Jilg C, Wilhelm K, Leiber C, Gerull S, Halter J, Lengerke C, Pabst T, Schroeder T, Kobbe G, Rösler W, Doostkam S, Meckel S, Stabla K, Metzelder SK, Halbach S, Brummer T, Hu Z, Dengjel J, Hackanson B, Schmid C, Holtick U, Scheid C, Spyridonidis A, Stoelzel F, Ordemann R, Mueller LP, Sicre-De-Fontbrune F, Ihorst G, Kuball J, Ehlert JE, Feger D, Wagner EM, Cahn JY, Schnell J, Kuchenbauer F, Bunjes D, Chakraverty R, Richardson S, Gill S, Kroeger N, Ayuk F, Vago L, Ciceri F, Mueller AM, Kondo T, Teshima T, Klaeger S, Kuster B, Kim DH, Weisdorf D, Van Der Velden W, Doerfel D, Bethge W, Hilgendorf I, Hochhaus A, Andrieux G, Boerries M, Busch H, Magenau J, Reddy P, Labopin M, Antin JH, Henden AS, Hill GR, Kennedy GA, Bar M, Sarma A, Mclornan D, Mufti G, Oran B, Rezvani K, Shah O, Negrin RS, Nagler A, Prinz M, Burchert A, Neubauer A, Beelen D, Mackensen A, Von Bubnoff N, Herr W, Becher B, Socie G, Caligiuri MA, Ruggiero E, Bonini C, Haecker G, Duyster J, Finke J, Pearce E, Blazar BR, Zeiser R
Journal: Nature Medicine
Publication year: 2018
ISSN: 1078-8956


Abstract

Individuals with acute myeloid leukemia (AML) harboring an internal tandem duplication (ITD) in the gene encoding Fms-related tyrosine kinase 3 (FLT3) who relapse after allogeneic hematopoietic cell transplantation (allo-HCT) have a 1-year survival rate below 20%. We observed that sorafenib, a multitargeted tyrosine kinase inhibitor, increased IL-15 production by FLT3-ITD+leukemia cells. This synergized with the allogeneic CD8+T cell response, leading to long-term survival in six mouse models of FLT3-ITD+AML. Sorafenib-related IL-15 production caused an increase in CD8+CD107a+IFN-γ+T cells with features of longevity (high levels of Bcl-2 and reduced PD-1 levels), which eradicated leukemia in secondary recipients. Mechanistically, sorafenib reduced expression of the transcription factor ATF4, thereby blocking negative regulation of interferon regulatory factor 7 (IRF7) activation, which enhanced IL-15 transcription. Both IRF7 knockdown and ATF4 overexpression in leukemia cells antagonized sorafenib-induced IL-15 production in vitro. Human FLT3-ITD+AML cells obtained from sorafenib responders following sorafenib therapy showed increased levels of IL-15, phosphorylated IRF7, and a transcriptionally active IRF7 chromatin state. The mitochondrial spare respiratory capacity and glycolytic capacity of CD8+T cells increased upon sorafenib treatment in sorafenib responders but not in nonresponders. Our findings indicate that the synergism of T cells and sorafenib is mediated via reduced ATF4 expression, causing activation of the IRF7-IL-15 axis in leukemia cells and thereby leading to metabolic reprogramming of leukemia-reactive T cells in humans. Therefore, sorafenib treatment has the potential to contribute to an immune-mediated cure of FLT3-ITD-mutant AML relapse, an otherwise fatal complication after allo-HCT.


FAU Authors / FAU Editors

Rösler, Wolf Dr. med.
Medizinische Klinik 5 - Hämatologie und Internistische Onkologie


External institutions with authors

Albert-Ludwigs-Universität Freiburg
Chaim Sheba Medical Center at Tel HaShomer / המרכז הרפואי ע"ש חיים שיבא – תל השומר‎‎
Charité - Universitätsmedizin Berlin
Deutsches Krebsforschungszentrum (DKFZ)
Goethe-Universität Frankfurt am Main
Harvard University
Hokkaido University (Hokudai) / 北海道大学
Hôpital Saint-Antoine
Hôpitaux Universitaires Saint-Louis, Lariboisière, Fernand-Widal
Inselspital, Universitätsspital Bern
King's College Hospital (KCH)
Klinikum Augsburg
Max-Planck-Institut für Immunbiologie und Epigenetik (MPI-IE) / Max Planck Institute of Immunobiology and Epigenetics
Ohio State University
Philipps-Universität Marburg
ProQinase GmbH
QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research)
Radboud University Nijmegen
Royal Brisbane and Women's Hospital
Royal Free Hospital
San Rafaele Scientific Institute
Stanford University
Technische Universität München (TUM)
Universitätsklinikum Bonn
Universitätsklinikum Carl Gustav Carus Dresden
Universitätsklinikum Düsseldorf
Universitätsklinikum Essen
Universitätsklinikum Halle (Saale)
Universitätsklinikum Hamburg-Eppendorf (UKE)
Universitätsklinikum Jena
Universitätsklinikum Köln
Universitätsklinikum Regensburg
Universitätsklinikum Tübingen
Universitätsklinikum Ulm
Universitätsmedizin der Johannes Gutenberg-Universität Mainz
Universitätsspital Basel
Universitätsspital Zürich (USZ)
Universität Zürich (UZH)
University Medical Centre Utrecht (UMC Utrecht)
University of Grenoble Alpes (UGA) / Université de Grenoble
University of Michigan
University of Minnesota (UMN)
University of Patras (UPATRAS)
University of Pennsylvania Health System (UPHS, Penn Medicine)
University of Texas MD Anderson Cancer Center
University of Toronto
University of Washington


How to cite

APA:
Mathew, N.R., Baumgartner, F., Braun, L., O'Sullivan, D., Thomas, S., Waterhouse, M.,... Zeiser, R. (2018). Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells. Nature Medicine. https://dx.doi.org/10.1038/nm.4484

MLA:
Mathew, Nimitha R., et al. "Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells." Nature Medicine (2018).

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Last updated on 2018-04-10 at 20:08