Inhibition of ITK differentiates GVT and GVHD in allo-HSCT

Author:

Mammadli Mahinbanu,Huang Weishan,Harris Rebecca,Sultana Aisha,Cheng Ying,Tong Wei,Pu Jeffery,Gentile Teresa,Henty-Ridilla Jessica,Dsouza Shanti,Yang Qi,August Avery,Bah Alaji,Karimi MobinORCID

Abstract

AbstractAllogeneic hematopoietic stem cell transplantation is a life-saving treatment for many malignant and nonmalignant diseases. Donor T cells contained within the graft prevent tumor recurrence via graft-versus-tumor (GVT) effects, however, also cause graft-versus-host disease (GVHD). Novel treatment strategies are therefore needed to allow maintenance of GVT while suppressing GVHD. Here we show using murine models, that targeting IL-2-inducible T cell kinase (ITK) in donor T cells reduces GVHD while preserving the beneficial GVT effects. Donor T cells from Itk-/- mice exhibit significantly reduced production of inflammatory cytokines and migration to GVHD target organs such as liver and small intestine, while maintaining GVT efficacy against primary B-ALL tumors. Itk-/- T cells exhibited reduced expression of IRF4 and decreased JAK/STAT signaling activity, but preserved cytotoxicity, which was accompanied by upregulation of Eomesodermin (Eomes), which was necessary for GVT function. A novel peptide inhibitor ITK signaling is also able to prevent GVHD. This novel peptide inhibitor also reduced cytokine production in mice and human T cells. Altogether, our data suggest that inhibiting ITK could be a therapeutic strategy to reduce GVHD while preserving the beneficial GVT effects following allo-HSCT treatment.Key PointsInhibiting ITK by a novel peptide significantly reduces GVHD but retains GVT.ITK deficient donor T cells exhibit minimal GVHD, but maintain GVT activity.ITK deficient donor T cells exhibit significantly reduced production of inflammatory cytokines and migration to GVHD target organs.Eomes is required for GVT effect.

Publisher

Cold Spring Harbor Laboratory

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