My research group, which is supported by the ERC grant, worked on the role of neutrophils in a disease called graft-versus-host disease (GVHD). The background of this project is that therapeutic interference with the early events of GVHD is difficult, and currently used immunosuppressive drugs mainly target donor T cells. A detailed analysis of neutrophil fate during acute GVHD and the effect on T cells is difficult because of the short lifespan of this cell type. We could show in this reporting period that neutrophils that had been photoconverted in the a section of the intestinal tract called ileum later migrated to lymph nodes located in close proximity to the intestines. We also observed that the neutrophils colocalized with T cells and presented antigen on major histocompatibility complex (MHC)-II, thereby affecting T cell expansion. We found that JAK1/JAK2 inhibition with a drug called ruxolitinib reduced neutrophil influx into the lymph nodes and acute GVHD pathogenesis.
Pathogenic kinase sinaling is not only found in immune cells that cause GVHD but also in leukemia cells that cause relapse after allo-HCT. 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 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. 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.
