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

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Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells.
Nature Medicine ( IF 58.7 ) Pub Date : 2018-Mar-01 , DOI: 10.1038/nm.4484
Nimitha R Mathew _{1,

2} , Francis Baumgartner ₁ , Lukas Braun ₁ , David O'Sullivan ₃ , Simone Thomas ₄ , Miguel Waterhouse ₁ , Tony A Müller ₁ , Kathrin Hanke _{1,

2} , Sanaz Taromi ₁ , Petya Apostolova ₁ , Anna L Illert ₁ , Wolfgang Melchinger ₁ , Sandra Duquesne ₁ , Annette Schmitt-Graeff ₅ , Lena Osswald ₁ , Kai-Li Yan ₁ , Arnim Weber ₆ , Sonia Tugues ₇ , Sabine Spath ₇ , Dietmar Pfeifer ₁ , Marie Follo ₁ , Rainer Claus ₁ , Michael Lübbert ₁ , Christoph Rummelt ₁ , Hartmut Bertz ₁ , Ralph Wäsch ₁ , Johanna Haag ₁ , Andrea Schmidts ₁ , Michael Schultheiss ₈ , Dominik Bettinger ₈ , Robert Thimme ₈ , Evelyn Ullrich ₉ , Yakup Tanriver _{6,

10} , Giang Lam Vuong ₁₁ , Renate Arnold ₁₁ , Philipp Hemmati ₁₁ , Dominik Wolf ₁₂ , Markus Ditschkowski ₁₃ , Cordula Jilg ₁₄ , Konrad Wilhelm ₁₄ , Christian Leiber ₁₄ , Sabine Gerull ₁₅ , Jörg Halter ₁₅ , Claudia Lengerke ₁₅ , Thomas Pabst ₁₆ , Thomas Schroeder ₁₇ , Guido Kobbe ₁₇ , Wolf Rösler ₁₈ , Soroush Doostkam ₁₉ , Stephan Meckel ₂₀ , Kathleen Stabla _{21,

22} , Stephan K Metzelder _{21,

22} , Sebastian Halbach ₂₃ , Tilman Brummer _{23,

24,

25,

26} , Zehan Hu _{27,

28} , Joern Dengjel _{27,

28} , Björn Hackanson ₂₉ , Christoph Schmid ₂₉ , Udo Holtick ₃₀ , Christof Scheid ₃₀ , Alexandros Spyridonidis ₃₁ , Friedrich Stölzel ₃₂ , Rainer Ordemann ₃₂ , Lutz P Müller ₃₃ , Flore Sicre-de-Fontbrune _{34,

35} , Gabriele Ihorst ₃₆ , Jürgen Kuball ₃₇ , Jan E Ehlert ₃₈ , Daniel Feger ₃₈ , Eva-Maria Wagner ₃₉ , Jean-Yves Cahn ₄₀ , Jacqueline Schnell ₄₁ , Florian Kuchenbauer ₄₁ , Donald Bunjes ₄₁ , Ronjon Chakraverty _{42,

43} , Simon Richardson _{42,

43} , Saar Gill ₄₄ , Nicolaus Kröger ₄₅ , Francis Ayuk ₄₅ , Luca Vago _{46,

47,

48} , Fabio Ciceri _{46,

47,

48} , Antonia M Müller ₄₉ , Takeshi Kondo ₅₀ , Takanori Teshima ₅₀ , Susan Klaeger _{26,

51} , Bernhard Kuster ₅₁ , Dennis Dong Hwan Kim ₅₂ , Daniel Weisdorf ₅₃ , Walter van der Velden ₅₄ , Daniela Dörfel ₅₅ , Wolfgang Bethge ₅₅ , Inken Hilgendorf ₅₆ , Andreas Hochhaus ₅₆ , Geoffroy Andrieux _{24,

26,

57} , Melanie Börries _{24,

26,

57} , Hauke Busch _{24,

26,

57,

58} , John Magenau ₅₉ , Pavan Reddy ₅₉ , Myriam Labopin ₆₀ , Joseph H Antin ₆₁ , Andrea S Henden _{62,

63} , Geoffrey R Hill _{62,

63,

64} , Glen A Kennedy ₆₄ , Merav Bar ₆₅ , Anita Sarma ₆₆ , Donal McLornan ₆₆ , Ghulam Mufti ₆₆ , Betul Oran ₆₇ , Katayoun Rezvani ₆₇ , Omid Shah ₆₈ , Robert S Negrin ₆₈ , Arnon Nagler ₆₉ , Marco Prinz _{20,

25} , Andreas Burchert ₂₃ , Andreas Neubauer _{21,

22} , Dietrich Beelen ₁₄ , Andreas Mackensen ₁₉ , Nikolas von Bubnoff ₁ , Wolfgang Herr ₄ , Burkhard Becher ₇ , Gerard Socié _{34,

35} , Michael A Caligiuri ₇₀ , Eliana Ruggiero _{46,

47,

48} , Chiara Bonini _{46,

47,

48} , Georg Häcker ₆ , Justus Duyster ₁ , Jürgen Finke ₁ , Erika Pearce ₃ , Bruce R Blazar ₇₁ , Robert Zeiser _{1,

25}

Affiliation

Department of Hematology, Oncology and Stem Cell Transplantation, Faculty of Medicine, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany.
Faculty of Biology, University of Freiburg, Freiburg, Germany.
Max Planck Institute for Immunobiology and Epigenetics, Freiburg, Germany.
Department of Internal Medicine III, Hematology and Oncology, University Hospital Regensburg, Regensburg, Germany.
Department of Pathology, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany.
Department of Medical Microbiology and Hygiene, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany.
Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
Department of Medicine II, Faculty of Medicine, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany.
Department for Children and Adolescents Medicine, Division of Stem Cell Transplantation and Immunology, University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt, Germany.
Department of Nephrology, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany.
Department of Stem Cell Transplantation, Charité University Medicine Berlin, Berlin, Germany.
Department of Hematology, University Medical Center Innsbruck, Austria.
Department of Bone Marrow Transplantation, West German Cancer Center, University Hospital Essen, Essen, Germany.
Department of Urology, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany.
Division of Hematology, University Hospital Basel, Basel, Switzerland.
Department of Internal Medicine, Inselspital/Universitätsspital Bern, Bern, Switzerland.
Department of Hematology, Oncology and Clinical Immunology, Universitätsklinikum, Düsseldorf, Düsseldorf, Germany.
Department of Hematology and Oncology, University of Erlangen, Erlangen, Germany.
Institute for Neuropathology, University of Freiburg, Freiburg, Germany.
Department of Neuroradiology, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany.
Department of Hematology, Oncology and Immunology, Philipps University Marburg, Marburg, Germany.
Department of Hematology, University Hospital of Giessen and Marburg, Marburg, Germany.
Institute of Molecular Medicine and Cell Research (IMMZ), Faculty of Medicine, University Medical Center Freiburg, University of Freiburg,Freiburg, Germany.
German Cancer Consortium (DKTK), Partner Site Freiburg, Freiburg, Germany.
Center for Biological Signaling Studies (BIOSS), University of Freiburg, Freiburg, Germany.
German Cancer Research Center (DKFZ), Heidelberg, Germany.
Department of Dermatology, University Medical Center, University of Freiburg, Freiburg, Germany.
Department of Biology, University of Fribourg, Fribourg, Switzerland.
Interdisciplinary Cancer Center Augsburg (ICCA) II, Clinic for Internal Medicine, Augsburg, Germany.
Department of Internal Medicine I, University Hospital Cologne, Cologne, Germany.
Hematology Stem Cell Transplant Unit, School of Medicine, University of Patras, Patras, Greece.
Department of Hematology and Oncology, Universitätsklinikum Carl Gustav Carus and Technischen Universität Dresden, Dresden, Germany.
Department of Hematology and Oncology, Universitätsklinikum Halle, Halle, Germany.
Assistance Publique-Hôpitaux de Paris, Hematology Stem Cell Transplantation, Saint Louis Hospital, Paris, France.
INSERM UMR 1160, Paris, France.
Clinical Trials Unit, Faculty of Medicine, University Medical Center, University of Freiburg, Freiburg, Germany.
Department of Hematology, University Medical Center Utrecht, Utrecht, the Netherlands.
ProQinase, Freiburg, Germany.
Department of Hematology and Oncology, Universitätsmedizin Mainz, Mainz, Germany.
Clinique Universitaire Hématologie, Université Grenoble Alpes, Grenoble, France.
Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany.
Cancer Institute, Royal Free Hospital, London, UK.
Institute of Immunity and Transplantation, Royal Free Hospital, London, UK.
Smilow Translational Research Center, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Department of Stem Cell Transplantation, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
Unit of Immunogenetics, Leukemia Genomics and Immunobiology, San Raffaele Scientific Institute, Milan, Italy.
Unit of Hematology and Bone Marrow Transplantation, San Raffaele Scientific Institute, Milan, Italy.
Department of Hematology, University Vita-Salute, San Raffaele University, Milan, Italy.
Department of Hematology, University Hospital Zurich, Zurich, Switzerland.
Department of Hematology, Hokkaido University, Sapporo, Japan.
Proteomics and Bioanalytics, Technische Universität München, Partner Site of the German Cancer Consortium, Freising, Germany.
Department of Medical Oncology & Hematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada.
Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, Minnesota, USA.
Department of Hematology, Radboud University, Nijmegen, the Netherlands.
Medizinische Klinik II, Universitätsklinikum Tübingen, Tübingen, Germany.
Klinik für Innere Medizin II, Universitätsklinikum Jena, Jena, Germany.
Systems Biology of the Cellular Microenvironment Group, IMMZ, ALU, Freiburg, Germany.
Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany.
Department of Hematology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
EBMT Statistical Unit, Hôpital Saint Antoine Paris, Paris, France.
Dana-Farber Cancer Institute, Harvard Medical School, Harvard University, Boston, Massachusetts, USA.
Bone Marrow Transplant Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Department of Haematology, Royal Brisbane Hospital, Brisbane, Queensland, Australia.
Department of Haematology, Royal Brisbane and Womens Hospital, Brisbane, Queensland, Australia.
Division of Blood and Marrow Transplantation, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washington, USA.
Department of Haematological Medicine, King's College Hospital NHS Foundation Trust, London, UK.
Division of Bone Marrow Transplantation, MD Anderson Cancer Center, Houston, Texas, USA.
Division of Blood and Marrow Transplantation, Stanford University Medical School, Stanford, California, USA.
Division of Hematology, Chaim Sheba Medical Center, Tel Hashomer, Israel.
Ohio State University Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, USA.
Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, Minnesota, USA.

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.

中文翻译：

索拉非尼通过 FLT3-ITD 突变白血病细胞中产生 IL-15 来促进小鼠和人类的移植物抗白血病活性。

编码 Fms 相关酪氨酸激酶 3 (FLT3) 的基因中含有内部串联重复 (ITD) 的急性髓系白血病 (AML) 患者，在同种异体造血细胞移植 (allo-HCT) 后复发，其 1 年生存率低于 20 %。我们观察到索拉非尼（一种多靶点酪氨酸激酶抑制剂）增加了 FLT3-ITD ⁺白血病细胞的 IL-15 产生。这与同种异体 CD8 ⁺ T 细胞反应协同作用，导致六种 FLT3-ITD ⁺ AML 小鼠模型长期存活。索拉非尼相关的 IL-15 产生导致 CD8 ⁺ CD107a ⁺ IFN-γ ⁺ T 细胞增加，具有长寿特征（高水平的 Bcl-2 和降低的 PD-1 水平），从而消除了二次受者的白血病。从机制上讲，索拉非尼降低了转录因子 ATF4 的表达，从而阻断了干扰素调节因子 7 (IRF7) 激活的负调节，从而增强了 IL-15 的转录。白血病细胞中 IRF7 敲低和 ATF4 过表达均可在体外拮抗索拉非尼诱导的 IL-15 产生。索拉非尼治疗后从索拉非尼应答者获得的人 FLT3-ITD ⁺ AML 细胞显示 IL-15、磷酸化 IRF7 和转录活性 IRF7 染色质状态水平升高。在索拉非尼治疗后，索拉非尼应答者的线粒体备用呼吸能力和 CD8 ⁺ T 细胞的糖酵解能力增加，但无应答者则没有增加。我们的研究结果表明，T 细胞和索拉非尼的协同作用是通过减少 ATF4 表达介导的，导致白血病细胞中 IRF7-IL-15 轴的激活，从而导致人类白血病反应性 T 细胞的代谢重编程。因此，索拉非尼治疗有可能有助于免疫介导治愈 FLT3-ITD 突变型 AML 复发，这是 allo-HCT 后致命的并发症。

更新日期：2018-02-13

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