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

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Abstract

Patients relapsing with FLT3-ITD mutant acute myeloid leukemia (AML) after allogeneic hematopoietic cell transplantation (allo-HCT) have a one-year-survival rate below 20%. We observed that sorafenib, a multi-tyrosine kinase inhibitor, increased IL-15 production by FLT3-ITD +-leukemia cells, which synergized with the allogeneic CD8 + T-cell response, leading to long-term survival in six mouse models of FLT3-ITD +AML. Sorafenib treatment-related IL-15 production caused an increase in CD8 +CD107a +IFN-γ + T-cells with features of longevity (Bcl-2 high, reduced PD-1-levels), which eradicated leukemia in secondary recipients. Mechanistically, sorafenib reduced expression of the transcription factor ATF4, thereby blocking negative regulation of 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 of sorafenib-responders obtained post sorafenib-therapy showed increased levels of IL-15, pIRF7, and a transcriptionally active IRF7-chromatin state. Mitochondrial spare respiratory capacity and glycolytic capacity of CD8 +T-cells increased upon sorafenib-treatment in sorafenib-responders but not in non-responders. 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 leading to metabolic reprogramming of leukemia-reactive T-cells in humans. Sorafenib treatment therefore 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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T cell metabolism drives immunity

Michael D Buck, David O’Sullivan, Erika L Pearce (2015)

Buck et al. discuss the role of lymphocyte metabolism on immune cell development and function.

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Graft-versus-host disease is enhanced by extracellular ATP activating P2X7R.

Konrad Wilhelm, Jayanthi Ganesan, Tobias Müller … (2010)

Danger signals released upon cell damage can cause excessive immune-mediated tissue destruction such as that found in acute graft-versus-host disease (GVHD), allograft rejection and systemic inflammatory response syndrome. Given that ATP is found in small concentrations in the extracellular space under physiological conditions, and its receptor P2X(7)R is expressed on several immune cell types, ATP could function as a danger signal when released from dying cells. We observed increased ATP concentrations in the peritoneal fluid after total body irradiation, and during the development of GVHD in mice and in humans. Stimulation of antigen-presenting cells (APCs) with ATP led to increased expression of CD80 and CD86 in vitro and in vivo and actuated a cascade of proinflammatory events, including signal transducer and activator of transcription-1 (STAT1) phosphorylation, interferon-γ (IFN-γ) production and donor T cell expansion, whereas regulatory T cell numbers were reduced. P2X(7)R expression increased when GVHD evolved, rendering APCs more responsive to the detrimental effects of ATP, thereby providing positive feedback signals. ATP neutralization, early P2X(7)R blockade or genetic deficiency of P2X(7)R during GVHD development improved survival without immune paralysis. These data have major implications for transplantation medicine, as pharmacological interference with danger signals that act via P2X(7)R could lead to the development of tolerance without the need for intensive immunosuppression.

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Neutrophil granulocytes recruited upon translocation of intestinal bacteria enhance graft-versus-host disease via tissue damage.

D von der Weid, Jürgen Finke, Marina Freudenberg … (2014)

Acute graft-versus-host disease (GVHD) considerably limits wider usage of allogeneic hematopoietic cell transplantation (allo-HCT). Antigen-presenting cells and T cells are populations customarily associated with GVHD pathogenesis. Of note, neutrophils are the largest human white blood cell population. The cells cleave chemokines and produce reactive oxygen species, thereby promoting T cell activation. Therefore, during an allogeneic immune response, neutrophils could amplify tissue damage caused by conditioning regimens. We analyzed neutrophil infiltration of the mouse ileum after allo-HCT by in vivo myeloperoxidase imaging and found that infiltration levels were dependent on the local microbial flora and were not detectable under germ-free conditions. Physical or genetic depletion of neutrophils reduced GVHD-related mortality. The contribution of neutrophils to GVHD severity required reactive oxygen species (ROS) because selective Cybb (encoding cytochrome b-245, beta polypeptide, also known as NOX2) deficiency in neutrophils impairing ROS production led to lower levels of tissue damage, GVHD-related mortality and effector phenotype T cells. Enhanced survival of Bcl-xL transgenic neutrophils increased GVHD severity. In contrast, when we transferred neutrophils lacking Toll-like receptor-2 (TLR2), TLR3, TLR4, TLR7 and TLR9, which are normally less strongly activated by translocating bacteria, into wild-type C57BL/6 mice, GVHD severity was reduced. In humans, severity of intestinal GVHD strongly correlated with levels of neutrophils present in GVHD lesions. This study describes a new potential role for neutrophils in the pathogenesis of GVHD in both mice and humans.