Background: 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. Methods: 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. Results: 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. Conclusions: 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.
背景：FMS样酪氨酸激酶3（FLT3）突变或内部串联重复发生在30%的急性髓系白血病（AML）病例中。针对此类病例，FLT3抑制剂（FLT3i）已被批准用于诱导治疗及复发治疗。对于符合条件的患者，异基因造血干细胞移植（alloHSCT）仍是推荐的诱导后治疗方案。然而，alloHSCT后FLT3i治疗的作用尚不明确。因此，我们研究了目前可用的三种FLT3i——吉瑞替尼、米哚妥林和奎扎替尼——对树突状细胞（DCs）的免疫抑制作用。DCs是专职抗原呈递细胞，能诱导T细胞对感染性刺激产生反应。高度活化的DCs也可能导致alloHSCT后的并发症，例如引发移植物抗宿主病，这是alloHSCT后一种严重且可能危及生命的并发症。方法：为研究FLT3i对DCs的免疫调节作用，我们在FLT3i存在条件下分化小鼠和人DCs，通过流式细胞术进行免疫表型分析、细胞因子检测，并研究基因和蛋白表达。结果：我们检测到米哚妥林具有剂量依赖性的免疫抑制作用，能降低CD86等共刺激标志物的表达，并发现促炎细胞因子如IL-12、TNFα和IL-6的分泌减少。机制上，我们发现米哚妥林能抑制TLR和TNF信号通路以及NFκB、PI3K和MAPK通路。吉瑞替尼的免疫抑制作用较弱，而奎扎替尼未显示对相关信号通路的截断作用。结论：我们的研究结果表明这三种FLT3i具有不同的免疫抑制作用，这可能为FLT3阳性AML患者alloHSCT后优化维持治疗、预防DCs介导的感染并发症和GvHD提供额外的理论依据。
The Immunomodulatory Effect of Different FLT3 Inhibitors on Dendritic Cells
肿瘤(癌症)患者之家