Article | Published:

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

Nature Medicine volume 24, pages 282291 (2018) | Download Citation

  • An Erratum to this article was published on 10 April 2018

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.

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Change history

  • Corrected online 06 March 2018

    In the version of this article initially published, Omid Shah’s name was misspelled as Omid Sha. The error has been corrected in the PDF and HTML versions of this article.

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Acknowledgements

We thank G. Prinz and H. Dierbach for their help with mouse experiments, K. Geiger and D. Herchenbach for cell sorting, and S. Decker (University of Freiburg) for providing NSG mice. We thank M.E.D. Flowers (University of Washington) for help with patient data. We thank D. Cittaro for the help with bioinformatic analysis. Il15−/− mice were provided by Y. Tanriver (University of Freiburg). Il15−/− mice were provided by B. Becher (University of Zurich).

This study was supported by the German Research Foundation (DFG) Heisenberg Professorship ZE 872/3-1 (R.Z.), DFG Sonderforschungsbereiche 1074 (SFB1074; F.K.), SFB1160 (R.Z.), SFB850 (T.B.), and TRR167 (R.Z.); European Research Council (ERC) Consolidator Grant no. 681012 GvHDCure (R.Z.); Deutsche Krebshilfe no. 111639 (G.H., R.Z.); Deutsche Jose Carreras Leukämie-Stiftung (DJCLS; G.H., R.Z.); Else Kröner-Fresenius Foundation (EKF) Stiftung no. 2015_A147 (P.A.), INTERREG V Rhin Supérieur (P.A., R.Z.); LOEWE–Gentherapie Frankfurt (CGT), Hessian Ministry of Higher Education, Research and the Arts, Germany no. III L 4- 518/17.004 (E.U.); Max-Eder-Nachwuchsgruppenprogramm, Deutsche Krebshilfe no. 109420 (F.K.); European Hematology Association fellowship 2010/04 (F.K.); and National Institutes of Health (NIH) grant no. R01 CA-72669 (B.R.B.). E.R. was supported by a fellowship from Associazione Italiana per la Ricerca sul Cancro (AIRC) that was cofunded by the European Union.

Author information

Affiliations

  1. Department of Hematology, Oncology and Stem Cell Transplantation, Faculty of Medicine, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany.

    • Nimitha R Mathew
    • , Francis Baumgartner
    • , Lukas Braun
    • , Miguel Waterhouse
    • , Tony A Müller
    • , Kathrin Hanke
    • , Sanaz Taromi
    • , Petya Apostolova
    • , Anna L Illert
    • , Wolfgang Melchinger
    • , Sandra Duquesne
    • , Lena Osswald
    • , Kai-Li Yan
    • , Dietmar Pfeifer
    • , Marie Follo
    • , Rainer Claus
    • , Michael Lübbert
    • , Christoph Rummelt
    • , Hartmut Bertz
    • , Ralph Wäsch
    • , Johanna Haag
    • , Andrea Schmidts
    • , Nikolas von Bubnoff
    • , Justus Duyster
    • , Jürgen Finke
    •  & Robert Zeiser
  2. Faculty of Biology, University of Freiburg, Freiburg, Germany.

    • Nimitha R Mathew
    •  & Kathrin Hanke
  3. Max Planck Institute for Immunobiology and Epigenetics, Freiburg, Germany.

    • David O'Sullivan
    •  & Erika Pearce
  4. Department of Internal Medicine III, Hematology and Oncology, University Hospital Regensburg, Regensburg, Germany.

    • Simone Thomas
    •  & Wolfgang Herr
  5. Department of Pathology, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany.

    • Annette Schmitt-Graeff
  6. Department of Medical Microbiology and Hygiene, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany.

    • Arnim Weber
    • , Yakup Tanriver
    •  & Georg Häcker
  7. Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.

    • Sonia Tugues
    • , Sabine Spath
    •  & Burkhard Becher
  8. Department of Medicine II, Faculty of Medicine, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany.

    • Michael Schultheiss
    • , Dominik Bettinger
    •  & Robert Thimme
  9. Department for Children and Adolescents Medicine, Division of Stem Cell Transplantation and Immunology, University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt, Germany.

    • Evelyn Ullrich
  10. Department of Nephrology, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany.

    • Yakup Tanriver
  11. Department of Stem Cell Transplantation, Charité University Medicine Berlin, Berlin, Germany.

    • Giang Lam Vuong
    • , Renate Arnold
    •  & Philipp Hemmati
  12. Medical Clinic III, Oncology, Hematology, Immunooncology and Rheumatology, University Hospital Bonn (UKB), Bonn, Germany.

  13. Department of Hematology, University Medical Center Innsbruck, Austria.

    • Dominik Wolf
  14. Department of Bone Marrow Transplantation, West German Cancer Center, University Hospital Essen, Essen, Germany.

    • Markus Ditschkowski
  15. Department of Urology, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany.

    • Cordula Jilg
    • , Konrad Wilhelm
    • , Christian Leiber
    •  & Dietrich Beelen
  16. Division of Hematology, University Hospital Basel, Basel, Switzerland.

    • Sabine Gerull
    • , Jörg Halter
    •  & Claudia Lengerke
  17. Department of Internal Medicine, Inselspital/Universitätsspital Bern, Bern, Switzerland.

    • Thomas Pabst
  18. Department of Hematology, Oncology and Clinical Immunology, Universitätsklinikum, Düsseldorf, Düsseldorf, Germany.

    • Thomas Schroeder
    •  & Guido Kobbe
  19. Department of Hematology and Oncology, University of Erlangen, Erlangen, Germany.

    • Wolf Rösler
  20. Institute for Neuropathology, University of Freiburg, Freiburg, Germany.

    • Soroush Doostkam
    •  & Andreas Mackensen
  21. Department of Neuroradiology, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany.

    • Stephan Meckel
    •  & Marco Prinz
  22. Department of Hematology, Oncology and Immunology, Philipps University Marburg, Marburg, Germany.

    • Kathleen Stabla
    • , Stephan K Metzelder
    •  & Andreas Neubauer
  23. Department of Hematology, University Hospital of Giessen and Marburg, Marburg, Germany.

    • Kathleen Stabla
    • , Stephan K Metzelder
    •  & Andreas Neubauer
  24. Institute of Molecular Medicine and Cell Research (IMMZ), Faculty of Medicine, University Medical Center Freiburg, University of Freiburg,Freiburg, Germany.

    • Sebastian Halbach
    • , Tilman Brummer
    •  & Andreas Burchert
  25. German Cancer Consortium (DKTK), Partner Site Freiburg, Freiburg, Germany.

    • Tilman Brummer
    • , Geoffroy Andrieux
    • , Melanie Börries
    •  & Hauke Busch
  26. Center for Biological Signaling Studies (BIOSS), University of Freiburg, Freiburg, Germany.

    • Tilman Brummer
    • , Marco Prinz
    •  & Robert Zeiser
  27. German Cancer Research Center (DKFZ), Heidelberg, Germany.

    • Tilman Brummer
    • , Susan Klaeger
    • , Geoffroy Andrieux
    • , Melanie Börries
    •  & Hauke Busch
  28. Department of Dermatology, University Medical Center, University of Freiburg, Freiburg, Germany.

    • Zehan Hu
    •  & Joern Dengjel
  29. Department of Biology, University of Fribourg, Fribourg, Switzerland.

    • Zehan Hu
    •  & Joern Dengjel
  30. Interdisciplinary Cancer Center Augsburg (ICCA) II, Clinic for Internal Medicine, Augsburg, Germany.

    • Björn Hackanson
    •  & Christoph Schmid
  31. Department of Internal Medicine I, University Hospital Cologne, Cologne, Germany.

    • Udo Holtick
    •  & Christof Scheid
  32. Hematology Stem Cell Transplant Unit, School of Medicine, University of Patras, Patras, Greece.

    • Alexandros Spyridonidis
  33. Department of Hematology and Oncology, Universitätsklinikum Carl Gustav Carus and Technischen Universität Dresden, Dresden, Germany.

    • Friedrich Stölzel
    •  & Rainer Ordemann
  34. Department of Hematology and Oncology, Universitätsklinikum Halle, Halle, Germany.

    • Lutz P Müller
  35. Assistance Publique—Hôpitaux de Paris, Hematology Stem Cell Transplantation, Saint Louis Hospital, Paris, France.

    • Flore Sicre-de-Fontbrune
    •  & Gerard Socié
  36. INSERM UMR 1160, Paris, France.

    • Flore Sicre-de-Fontbrune
    •  & Gerard Socié
  37. Clinical Trials Unit, Faculty of Medicine, University Medical Center, University of Freiburg, Freiburg, Germany.

    • Gabriele Ihorst
  38. Department of Hematology, University Medical Center Utrecht, Utrecht, the Netherlands.

    • Jürgen Kuball
  39. ProQinase, Freiburg, Germany.

    • Jan E Ehlert
    •  & Daniel Feger
  40. Department of Hematology and Oncology, Universitätsmedizin Mainz, Mainz, Germany.

    • Eva-Maria Wagner
  41. Clinique Universitaire Hématologie, Université Grenoble Alpes, Grenoble, France.

    • Jean-Yves Cahn
  42. Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany.

    • Jacqueline Schnell
    • , Florian Kuchenbauer
    •  & Donald Bunjes
  43. Cancer Institute, Royal Free Hospital, London, UK.

    • Ronjon Chakraverty
    •  & Simon Richardson
  44. Institute of Immunity and Transplantation, Royal Free Hospital, London, UK.

    • Ronjon Chakraverty
    •  & Simon Richardson
  45. Smilow Translational Research Center, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Saar Gill
  46. Department of Stem Cell Transplantation, University Hospital Hamburg-Eppendorf, Hamburg, Germany.

    • Nicolaus Kröger
    •  & Francis Ayuk
  47. Unit of Immunogenetics, Leukemia Genomics and Immunobiology, San Raffaele Scientific Institute, Milan, Italy.

    • Luca Vago
    • , Fabio Ciceri
    • , Eliana Ruggiero
    •  & Chiara Bonini
  48. Unit of Hematology and Bone Marrow Transplantation, San Raffaele Scientific Institute, Milan, Italy.

    • Luca Vago
    • , Fabio Ciceri
    • , Eliana Ruggiero
    •  & Chiara Bonini
  49. Department of Hematology, University Vita-Salute, San Raffaele University, Milan, Italy.

    • Luca Vago
    • , Fabio Ciceri
    • , Eliana Ruggiero
    •  & Chiara Bonini
  50. Department of Hematology, University Hospital Zurich, Zurich, Switzerland.

    • Antonia M Müller
  51. Department of Hematology, Hokkaido University, Sapporo, Japan.

    • Takeshi Kondo
    •  & Takanori Teshima
  52. Proteomics and Bioanalytics, Technische Universität München, Partner Site of the German Cancer Consortium, Freising, Germany.

    • Susan Klaeger
    •  & Bernhard Kuster
  53. Department of Medical Oncology & Hematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada.

    • Dennis (Dong Hwan) Kim
  54. Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, Minnesota, USA.

    • Daniel Weisdorf
  55. Department of Hematology, Radboud University, Nijmegen, the Netherlands.

    • Walter van der Velden
  56. Medizinische Klinik II, Universitätsklinikum Tübingen, Tübingen, Germany.

    • Daniela Dörfel
    •  & Wolfgang Bethge
  57. Klinik für Innere Medizin II, Universitätsklinikum Jena, Jena, Germany.

    • Inken Hilgendorf
    •  & Andreas Hochhaus
  58. Systems Biology of the Cellular Microenvironment Group, IMMZ, ALU, Freiburg, Germany.

    • Geoffroy Andrieux
    • , Melanie Börries
    •  & Hauke Busch
  59. Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany.

    • Hauke Busch
  60. Department of Hematology, University of Michigan Medical School, Ann Arbor, Michigan, USA.

    • John Magenau
    •  & Pavan Reddy
  61. EBMT Statistical Unit, Hôpital Saint Antoine Paris, Paris, France.

    • Myriam Labopin
  62. Dana-Farber Cancer Institute, Harvard Medical School, Harvard University, Boston, Massachusetts, USA.

    • Joseph H Antin
  63. Bone Marrow Transplant Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.

    • Andrea S Henden
    •  & Geoffrey R Hill
  64. Department of Haematology, Royal Brisbane Hospital, Brisbane, Queensland, Australia.

    • Andrea S Henden
    •  & Geoffrey R Hill
  65. Department of Haematology, Royal Brisbane and Womens Hospital, Brisbane, Queensland, Australia.

    • Geoffrey R Hill
    •  & Glen A Kennedy
  66. Division of Blood and Marrow Transplantation, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washington, USA.

    • Merav Bar
  67. Department of Haematological Medicine, King's College Hospital NHS Foundation Trust, London, UK.

    • Anita Sarma
    • , Donal McLornan
    •  & Ghulam Mufti
  68. Division of Bone Marrow Transplantation, MD Anderson Cancer Center, Houston, Texas, USA.

    • Betul Oran
    •  & Katayoun Rezvani
  69. Division of Blood and Marrow Transplantation, Stanford University Medical School, Stanford, California, USA.

    • Omid Shah
    •  & Robert S Negrin
  70. Division of Hematology, Chaim Sheba Medical Center, Tel Hashomer, Israel.

    • Arnon Nagler
  71. Ohio State University Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, USA.

    • Michael A Caligiuri
  72. Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, Minnesota, USA.

    • Bruce R Blazar

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Contributions

N.R.M. performed the majority of the experiments, helped develop the overall concept behind the study, and helped write the manuscript. F.B. helped with the experiments and with development of the overall concept behind the study. L.B. performed ATF4 overexpression experiments. D.O'S. helped with Seahorse analysis. S. Thomas and S. Tugues helped with mouse experiments. M.W., T.A.M., K.H., P.A., A.L.I., G.I., K.S., W.M., S. Duqusne and A.W. helped with experiments and data interpretation. A.S.-G. performed immunohistological analysis. L.O. and K.-L.Y. helped with experiments. D.P., M.F., R. Claus, M. Lübbert, C.R., H. Bertz, R.W., J.H., A. Schmidts, M.S., D. Bettinger, R.T., E.U., Y.T., G.L.V., R.A., P.H., D. Wolf, M.D., C.J., K.W., C. Leiber, S. Gerull, J.H., C. Lengerke, T.P., T.S., G.K., W.R., S. Doostkam, S.M., and S.K.M. provided patient data. S. Taromi, S.S., and B.B. helped with mouse experiments. S.H. and T.B. helped with western blot and knockdown experiments. Z.H. and J. Dengjel performed mass spectrometry and data analysis. S.K. and B.K. performed mass spectrometry of sorafenib binding partners and kinome analysis. B.H., C. Schmid, U.H., C. Scheid, A. Spyridonidis, F.S., R.O., L.P.M., F.S.-d.-F., and J.K. provided patient data and helped with the analysis. M.P. performed analysis of the biopsy specimen. A.B., A. Nagler, D. Bunjes, A.M., W.H., and G.S. provided patient data and helped develop the overall concept behind the study. J.E.E. and D.F. analyzed the level of FLT3 inhibition upon sorafenib exposure. E.-M.W., J.-Y.C., F.K., D. Beelen, R. Chakraverty, S.R., S. Gill, N.K., F.A., L.V., J.S., and F.C. provided and analyzed patient data. E.R. and C.B. performed TRC sequencing and analyzed related data. A.M.M., T.K., T.T., B.K., D.K., D. Weisdorf, W.v.d.V., D.D., W.B., I.H., A.H., G.A., M. Börries, H. Busch, J.M., P.R., M. Labopin, J.H.A., A.S.H., G.R.H., G.A.K., M. Bar, A. Sarma, D.M., G.M., B.O., K.R., O.S., R.S.N., and A. Neubauer provided and analyzed patient data. E.U. and M.A.C. provided reagents and contributed to the development of the concept behind the study and the manuscript. B.R.B., N.v.B., and G.H. provided reagents, helped with the experiments, and analyzed data. E.P. helped to plan and analyze the T cell metabolism experiments. J. Duyster and J.F. helped develop the concept behind the study, analyze the data, and write the manuscript. R.Z. developed the overall concept behind the study, supervised the experiments, analyzed the data, and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Robert Zeiser.

Supplementary information

PDF files

  1. 1.

    Supplementary Figures & Tables

    Supplementary Figures 1–21 & Supplementary Tables 2–12

  2. 2.

    Life Sciences Reporting Summary

Excel files

  1. 1.

    Supplementary Table 1

    Patients raw data

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nm.4484