Targeting Interleukin-2-Inducible T-cell Kinase (ITK) differentiates GVL and GVHD in allo-HSCT

Allogeneic hematopoietic stem cell transplantation is a potentially curative procedure for many malignant diseases. Donor T cells prevent disease recurrence via graft-versus-leukemia (GVL) effect. Donor T cells also contribute to graft-versus-host disease (GVHD), a debilitating and potentially fatal complication. Novel treatment strategies are needed which allow preservation of GVL effects without causing GVHD. Using murine models, we show that targeting IL-2-inducible T cell kinase (ITK) in donor T cells reduces GVHD while preserving GVL effects. Both CD8+ and CD4+ donor T cells from Itk-/- mice produce less inflammatory cytokines and show decrease migration to GVHD target organs such as the liver and small intestine, while maintaining GVL efficacy against primary B-cell acute lymphoblastic leukemia (B-ALL). Itk-/- T cells exhibit reduced expression of IRF4 and decreased JAK/STAT signaling activity, but upregulating expression of Eomesodermin (Eomes) and preserve cytotoxicity, necessary for GVL effect. Transcriptome analysis indicates that ITK signaling controls chemokine receptor expression during alloactivation, which in turn affects the ability of donor T cells to migrate to GVHD target organs. Our data suggest that inhibiting ITK could be a therapeutic strategy to reduce GVHD while preserving the beneficial GVL effects following allo-HSCT treatment.

异基因造血干细胞移植（Allogeneic hematopoietic stem cell transplantation）是多种恶性疾病的潜在治愈性治疗手段。供体T细胞可通过移植物抗白血病（graft-versus-leukemia, GVL）效应预防疾病复发，但同时也会介导移植物抗宿主病（graft-versus-host disease, GVHD）——一种具有致残性且可能致命的并发症。因此，亟需开发能够保留GVL效应同时又不会诱发GVHD的新型治疗策略。本研究利用小鼠模型证实，在供体T细胞中靶向抑制白细胞介素2诱导性T细胞激酶（IL-2-inducible T cell kinase, ITK），可在减轻GVHD的同时保留GVL效应。来自ITK基因敲除（Itk-/-）小鼠的CD8阳性与CD4阳性供体T细胞，均能产生更少的炎性细胞因子，且向肝脏、小肠等GVHD靶器官的迁移能力显著降低，同时仍可维持对原发性B细胞急性淋巴细胞白血病（B-cell acute lymphoblastic leukemia, B-ALL）的GVL杀伤活性。ITK基因敲除的T细胞表现出干扰素调节因子4（IRF4）表达下调以及JAK/STAT信号通路活性减弱，同时会上调Eomesodermin（Eomes）的表达，并维持GVL效应所必需的细胞毒性功能。转录组分析结果显示，ITK信号通路在同种异体激活过程中调控趋化因子受体的表达，进而影响供体T细胞向GVHD靶器官迁移的能力。本研究数据表明，抑制ITK有望成为一种新型治疗手段，在异基因造血干细胞移植术后减轻GVHD的同时保留有益的GVL效应。