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Nat Med. 2018 Mar;24(3):282-291. doi: 10.1038/nm.4484. Epub 2018 Feb 12.

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

Mathew NR1,2, Baumgartner F1, Braun L1, O'Sullivan D3, Thomas S4, Waterhouse M1, Müller TA1, Hanke K1,2, Taromi S1, Apostolova P1, Illert AL1, Melchinger W1, Duquesne S1, Schmitt-Graeff A5, Osswald L1, Yan KL1, Weber A6, Tugues S7, Spath S7, Pfeifer D1, Follo M1, Claus R1, Lübbert M1, Rummelt C1, Bertz H1, Wäsch R1, Haag J1, Schmidts A1, Schultheiss M8, Bettinger D8, Thimme R8, Ullrich E9, Tanriver Y6,10, Vuong GL11, Arnold R11, Hemmati P11, Wolf D12, Ditschkowski M13, Jilg C14, Wilhelm K14, Leiber C14, Gerull S15, Halter J15, Lengerke C15, Pabst T16, Schroeder T17, Kobbe G17, Rösler W18, Doostkam S19, Meckel S20, Stabla K21,22, Metzelder SK21,22, Halbach S23, Brummer T23,24,25,26, Hu Z27,28, Dengjel J27,28, Hackanson B29, Schmid C29, Holtick U30, Scheid C30, Spyridonidis A31, Stölzel F32, Ordemann R32, Müller LP33, Sicre-de-Fontbrune F34,35, Ihorst G36, Kuball J37, Ehlert JE38, Feger D38, Wagner EM39, Cahn JY40, Schnell J41, Kuchenbauer F41, Bunjes D41, Chakraverty R42,43, Richardson S42,43, Gill S44, Kröger N45, Ayuk F45, Vago L46,47,48, Ciceri F46,47,48, Müller AM49, Kondo T50, Teshima T50, Klaeger S26,51, Kuster B51, Kim DDH52, Weisdorf D53, van der Velden W54, Dörfel D55, Bethge W55, Hilgendorf I56, Hochhaus A56, Andrieux G24,26,57, Börries M24,26,57, Busch H24,26,57,58, Magenau J59, Reddy P59, Labopin M60, Antin JH61, Henden AS62,63, Hill GR62,63,64, Kennedy GA64, Bar M65, Sarma A66, McLornan D66, Mufti G66, Oran B67, Rezvani K67, Shah O68, Negrin RS68, Nagler A69, Prinz M20,25, Burchert A23, Neubauer A21,22, Beelen D14, Mackensen A19, von Bubnoff N1, Herr W4, Becher B7, Socié G34,35, Caligiuri MA70, Ruggiero E46,47,48, Bonini C46,47,48, Häcker G6, Duyster J1, Finke J1, Pearce E3, Blazar BR71, Zeiser R1,25.

Author information

1
Department of Hematology, Oncology and Stem Cell Transplantation, Faculty of Medicine, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany.
2
Faculty of Biology, University of Freiburg, Freiburg, Germany.
3
Max Planck Institute for Immunobiology and Epigenetics, Freiburg, Germany.
4
Department of Internal Medicine III, Hematology and Oncology, University Hospital Regensburg, Regensburg, Germany.
5
Department of Pathology, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany.
6
Department of Medical Microbiology and Hygiene, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany.
7
Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
8
Department of Medicine II, Faculty of Medicine, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany.
9
Department for Children and Adolescents Medicine, Division of Stem Cell Transplantation and Immunology, University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt, Germany.
10
Department of Nephrology, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany.
11
Department of Stem Cell Transplantation, Charité University Medicine Berlin, Berlin, Germany.
12
Department of Hematology, University Medical Center Innsbruck, Austria.
13
Department of Bone Marrow Transplantation, West German Cancer Center, University Hospital Essen, Essen, Germany.
14
Department of Urology, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany.
15
Division of Hematology, University Hospital Basel, Basel, Switzerland.
16
Department of Internal Medicine, Inselspital/Universitätsspital Bern, Bern, Switzerland.
17
Department of Hematology, Oncology and Clinical Immunology, Universitätsklinikum, Düsseldorf, Düsseldorf, Germany.
18
Department of Hematology and Oncology, University of Erlangen, Erlangen, Germany.
19
Institute for Neuropathology, University of Freiburg, Freiburg, Germany.
20
Department of Neuroradiology, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany.
21
Department of Hematology, Oncology and Immunology, Philipps University Marburg, Marburg, Germany.
22
Department of Hematology, University Hospital of Giessen and Marburg, Marburg, Germany.
23
Institute of Molecular Medicine and Cell Research (IMMZ), Faculty of Medicine, University Medical Center Freiburg, University of Freiburg,Freiburg, Germany.
24
German Cancer Consortium (DKTK), Partner Site Freiburg, Freiburg, Germany.
25
Center for Biological Signaling Studies (BIOSS), University of Freiburg, Freiburg, Germany.
26
German Cancer Research Center (DKFZ), Heidelberg, Germany.
27
Department of Dermatology, University Medical Center, University of Freiburg, Freiburg, Germany.
28
Department of Biology, University of Fribourg, Fribourg, Switzerland.
29
Interdisciplinary Cancer Center Augsburg (ICCA) II, Clinic for Internal Medicine, Augsburg, Germany.
30
Department of Internal Medicine I, University Hospital Cologne, Cologne, Germany.
31
Hematology Stem Cell Transplant Unit, School of Medicine, University of Patras, Patras, Greece.
32
Department of Hematology and Oncology, Universitätsklinikum Carl Gustav Carus and Technischen Universität Dresden, Dresden, Germany.
33
Department of Hematology and Oncology, Universitätsklinikum Halle, Halle, Germany.
34
Assistance Publique-Hôpitaux de Paris, Hematology Stem Cell Transplantation, Saint Louis Hospital, Paris, France.
35
INSERM UMR 1160, Paris, France.
36
Clinical Trials Unit, Faculty of Medicine, University Medical Center, University of Freiburg, Freiburg, Germany.
37
Department of Hematology, University Medical Center Utrecht, Utrecht, the Netherlands.
38
ProQinase, Freiburg, Germany.
39
Department of Hematology and Oncology, Universitätsmedizin Mainz, Mainz, Germany.
40
Clinique Universitaire Hématologie, Université Grenoble Alpes, Grenoble, France.
41
Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany.
42
Cancer Institute, Royal Free Hospital, London, UK.
43
Institute of Immunity and Transplantation, Royal Free Hospital, London, UK.
44
Smilow Translational Research Center, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
45
Department of Stem Cell Transplantation, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
46
Unit of Immunogenetics, Leukemia Genomics and Immunobiology, San Raffaele Scientific Institute, Milan, Italy.
47
Unit of Hematology and Bone Marrow Transplantation, San Raffaele Scientific Institute, Milan, Italy.
48
Department of Hematology, University Vita-Salute, San Raffaele University, Milan, Italy.
49
Department of Hematology, University Hospital Zurich, Zurich, Switzerland.
50
Department of Hematology, Hokkaido University, Sapporo, Japan.
51
Proteomics and Bioanalytics, Technische Universität München, Partner Site of the German Cancer Consortium, Freising, Germany.
52
Department of Medical Oncology & Hematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada.
53
Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, Minnesota, USA.
54
Department of Hematology, Radboud University, Nijmegen, the Netherlands.
55
Medizinische Klinik II, Universitätsklinikum Tübingen, Tübingen, Germany.
56
Klinik für Innere Medizin II, Universitätsklinikum Jena, Jena, Germany.
57
Systems Biology of the Cellular Microenvironment Group, IMMZ, ALU, Freiburg, Germany.
58
Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany.
59
Department of Hematology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
60
EBMT Statistical Unit, Hôpital Saint Antoine Paris, Paris, France.
61
Dana-Farber Cancer Institute, Harvard Medical School, Harvard University, Boston, Massachusetts, USA.
62
Bone Marrow Transplant Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
63
Department of Haematology, Royal Brisbane Hospital, Brisbane, Queensland, Australia.
64
Department of Haematology, Royal Brisbane and Womens Hospital, Brisbane, Queensland, Australia.
65
Division of Blood and Marrow Transplantation, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washington, USA.
66
Department of Haematological Medicine, King's College Hospital NHS Foundation Trust, London, UK.
67
Division of Bone Marrow Transplantation, MD Anderson Cancer Center, Houston, Texas, USA.
68
Division of Blood and Marrow Transplantation, Stanford University Medical School, Stanford, California, USA.
69
Division of Hematology, Chaim Sheba Medical Center, Tel Hashomer, Israel.
70
Ohio State University Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, USA.
71
Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, Minnesota, USA.

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.

PMID:
29431743
PMCID:
PMC6029618
DOI:
10.1038/nm.4484
[Indexed for MEDLINE]
Free PMC Article

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