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

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 (2018)

Publication Type: Journal article

Publication year: 2018

Journal

DOI: 10.1038/nm.4484

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.

Authors with CRIS profile

Involved external institutions

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

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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