期刊
NATURE MEDICINE
卷 24, 期 3, 页码 282-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.4484
关键词
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资金
- German Research Foundation (DFG) Heisenberg Professorship [ZE 872/3-1]
- DFG Sonderforschungsbereiche [SFB1074, SFB1160, SFB850, TRR167]
- European Research Council (ERC) Consolidator [681012]
- Deutsche Krebshilfe [111639]
- Deutsche Jose Carreras Leukamie-Stiftung (DJCLS)
- Else Kroner-Fresenius Foundation (EKF) [2015_ A147]
- INTERREG V Rhin Superieur
- LOEWE-Gentherapie Frankfurt (CGT), Hessian Ministry of Higher Education, Research and the Arts, Germany [III L 4-518/17.004]
- Max-Eder-Nachwuchsgruppenprogramm, Deutsche Krebshilfe [109420]
- European Hematology Association fellowship [2010/04]
- National Institutes of Health (NIH) [R01 CA-72669]
- Associazione Italiana per la Ricerca sul Cancro (AIRC)
- European Union
- Cancer Research UK
- Versus Arthritis [20265] Funding Source: researchfish
- National Institute for Health Research [CL-2016-18-002] Funding Source: researchfish
- European Research Council (ERC) [681012] Funding Source: European Research Council (ERC)
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-gamma(+) 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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