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

NR Mathew, F Baumgartner, L Braun, D O'Sullivan, S Thomas, M Waterhouse, TA Müller, K Hanke, S Taromi, P Apostolova, AL Illert, W Melchinger, S Duquesne, A Schmitt-Graeff, L Osswald, KL Yan, A Weber, S Tugues, S Spath, D PfeiferM Follo, R Claus, M Lübbert, C Rummelt, H Bertz, R Wäsch, J Haag, A Schmidts, M Schultheiss, D Bettinger, R Thimme, E Ullrich, Y Tanriver, GL Vuong, R Arnold, P Hemmati, D Wolf, M Ditschkowski, C Jilg, K Wilhelm, C Leiber, S Gerull, J Halter, C Lengerke, T Pabst, T Schroeder, G Kobbe, W Rösler, S Doostkam, S Meckel, K Stabla, SK Metzelder, S Halbach, T Brummer, Z Hu, J Dengjel, B Hackanson, C Schmid, U Holtick, C Scheid, A Spyridonidis, F Stölzel, R Ordemann, LP Müller, F Sicre-de-Fontbrune, G Ihorst, J Kuball, JE Ehlert, D Feger, EM Wagner, JY Cahn, J Schnell, F Kuchenbauer, D Bunjes, R Chakraverty, S Richardson, S Gill, N Kröger, F Ayuk, L Vago, F Ciceri, AM Müller, T Kondo, T Teshima, S Klaeger, B Kuster, DDH Kim, D Weisdorf, W van der Velden, D Dörfel, W Bethge, I Hilgendorf, A Hochhaus, G Andrieux, M Börries, H Busch, J Magenau, P Reddy, M Labopin, JH Antin, AS Henden, GR Hill, GA Kennedy, M Bar, A Sarma, D McLornan, G Mufti, B Oran, K Rezvani, O Shah, RS Negrin, A Nagler, M Prinz, A Burchert, A Neubauer, D Beelen, A Mackensen, N von Bubnoff, W Herr, B Becher, G Socié, MA Caligiuri, E Ruggiero, C Bonini, G Häcker, J Duyster, J Finke, E Pearce, BR Blazar, R Zeiser

Research output: Contribution to journalArticle

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-3 + 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. © 2018 Nature America, Inc., part of Springer Nature. All rights reserved.
Original languageEnglish
Pages (from-to)282-291
Number of pages10
JournalNature Medicine
Volume24
Issue number3
DOIs
Publication statusPublished - 2018

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    Mathew, NR., Baumgartner, F., Braun, L., O'Sullivan, D., Thomas, S., Waterhouse, M., Müller, 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., ... 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, 24(3), 282-291. https://doi.org/10.1038/nm.4484