The Immunomodulatory Effect of Different FLT3 Inhibitors on Dendritic Cells.

Abstract

FMS-like tyrosine kinase 3 (FLT3) mutations or internal tandem duplication occur in 30% of acute myeloid leukemia (AML) cases. In these cases, FLT3 inhibitors (FLT3i) are approved for induction treatment and relapse. Allogeneic hematopoietic stem cell transplantation (alloHSCT) remains the recommended post-induction therapy for suitable patients. However, the role of FLT3i therapy after alloHSCT remains unclear. Therefore, we investigated the three currently available FLT3i, gilteritinib, midostaurin, and quizartinib, in terms of their immunosuppressive effect on dendritic cells (DCs). DCs are professional antigen-presenting cells inducing T-cell responses to infectious stimuli. Highly activated DCs can also cause complications after alloHSCT, such as triggering Graft versus Host disease, a serious and potentially life-threatening complication after alloHSCT. To study the immunomodulatory effects on DCs, we differentiated murine and human DCs in the presence of FLT3i and performed immunophenotyping by flow cytometry and cytokine measurements and investigated gene and protein expression. We detected a dose-dependent immunosuppressive effect of midostaurin, which decreased the expression of costimulatory markers like CD86, and found a reduced secretion of pro-inflammatory cytokines such as IL-12, TNFα, and IL-6. Mechanistically, we show that midostaurin inhibits TLR and TNF signaling and NFκB, PI3K, and MAPK pathways. The immunosuppressive effect of gilteritinib was less pronounced, while quizartinib did not show truncation of relevant signaling pathways. Our results suggest different immunosuppressive effects of these three FLT3i and may, therefore, provide an additional rationale for optimal maintenance therapy after alloHSCT of FLT3-positive AML patients to prevent infectious complications and GvHD mediated by DCs.