Journal Article

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

Bertz, Hartmut, Tanriver, Yakup, Ullrich, Evelyn, Braun, Lukas, Müller, Tony A, Osswald, Lena, Metzelder, Stephan K, Schroeder, Thomas, Neubauer, Andreas, Schnell, Jacqueline, Duyster, Justus, Yan, Kai-Li, Ehlert, Jan E, Wäsch, Ralph, Follo, Marie, Halter, Jörg, Henden, Andrea S, Schmitt-Graeff, Annette, Kobbe, Guido, Bonini, Chiara, Halbach, Sebastian, Shah, Omid, Dengjel, Joern, Kröger, Nicolaus, Pfeifer, Dietmar, Apostolova, Petya, van der Velden, Walter, Labopin, Myriam, Schmid, Christoph, Ruggiero, Eliana, Andrieux, Geoffroy, Antin, Joseph H, Mufti, Ghulam, Ditschkowski, Markus, Kennedy, Glen A, Waterhouse, Miguel, Feger, Daniel, Holtick, Udo, Börries, Melanie, O'Sullivan, David, Kuchenbauer, Florian, Reddy, Pavan, Ciceri, Fabio, Weisdorf, Daniel, Claus, Rainer, Magenau, John, Burchert, Andreas, Zeiser, Robert, Thimme, Robert, Pearce, Erika, Schmidts, Andrea, Mathew, Nimitha R, Spyridonidis, Alexandros, Sicre-de-Fontbrune, Flore, Doostkam, Soroush, Ihorst, Gabriele, Negrin, Robert S, Hemmati, Philipp, Gerull, Sabine, Herr, Wolfgang, Lübbert, Michael, Stölzel, Friedrich, Arnold, Renate, Scheid, Christof, Mc

2018

Overview

Combining the kinase inhibitor sorafenib with allogeneic stem cell transplantation boosts immune responses against a subtype of acute myelogenous leukemia, suggesting potential clinical benefit. 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 13 / 13/31 / 38/5 / 38/61 / 64/110 / 692/308 / 692/308/575 / Activating transcription factor 4 / Activating Transcription Factor 4 - genetics / Acute myelocytic leukemia / Acute myeloid leukemia / Allografts / Animal models / Animals / Bcl-2 protein / Biomedicine / Cancer Research / CD8 antigen / CD8-Positive T-Lymphocytes - immunology / Cell activation / Cell culture / Cell survival / Cells / Cellular Reprogramming - genetics / Chromatin / Development and progression / Drug therapy / Enzyme inhibitors / Flexible manufacturing systems / fms-Like Tyrosine Kinase 3 - genetics / Gene expression / Gene Expression Regulation, Neoplastic - drug effects / Gene mutation / Gene regulation / Genetic aspects / Glycolysis / Graft vs Host Disease - drug therapy / Graft vs Host Disease - genetics / Graft vs Host Disease - pathology / Health aspects / Hematopoietic Stem Cell Transplantation - adverse effects / Hematopoietic stem cells / Humans / Infectious Diseases / Inhibitor drugs / Interferon / Interferon regulatory factor / Interferon regulatory factor 7 / Interferon Regulatory Factor-7 - genetics / Interleukin 15 / Interleukin-15 - genetics / Kinases / Leukemia / Leukemia, Myeloid, Acute - drug therapy / Leukemia, Myeloid, Acute - genetics / Leukemia, Myeloid, Acute - pathology / Lymphocytes / Lymphocytes T / Metabolic Diseases / Metabolic rate / Mice / Mitochondria / Molecular Medicine / Mutants / Myeloid leukemia / Neurosciences / Patient outcomes / PD-1 protein / Protein-tyrosine kinase / Rodents / Sorafenib / Sorafenib - administration & dosage / Sorafenib - adverse effects / Stem cell transplantation / Stem cells / Survival / Synergism / Tandem Repeat Sequences - genetics / Targeted cancer therapy / Transcription activation / Transplantation / Transplantation, Homologous - adverse effects / Tyrosine / γ-Interferon