Research ArticleTransplantation

Targeting Aurora kinase A and JAK2 prevents GVHD while maintaining Treg and antitumor CTL function

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Science Translational Medicine  11 Jan 2017:
Vol. 9, Issue 372, eaai8269
DOI: 10.1126/scitranslmed.aai8269

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Guiding T cells to stem GVHD

Donor T cell–mediated graft-versus-host disease (GVHD) is a serious complication of stem cell transplantation, but complete inhibition of T cell activation might leave the patient susceptible to leukemia relapse. Betts et al. targeted two kinases involved in T cell costimulation and cytokine-responsiveness to blunt T cell responses. Dual targeting drove human CD4 T cells to become potently suppressive T regulatory cells instead of TH17 effector cells and also prevented GVHD in a humanized mouse model. CD8 T cells were capable of activation after a tumor challenge, indicating that patients receiving this treatment might be able to mount antileukemia responses.

Abstract

Graft-versus-host disease (GVHD) is a leading cause of nonrelapse mortality after allogeneic hematopoietic cell transplantation. T cell costimulation by CD28 contributes to GVHD, but prevention is incomplete when targeting CD28, downstream mammalian target of rapamycin (mTOR), or Aurora A. Likewise, interleukin-6 (IL-6)–mediated Janus kinase 2 (JAK2) signaling promotes alloreactivity, yet JAK2 inhibition does not eliminate GVHD. We provide evidence that blocking Aurora A and JAK2 in human T cells is synergistic in vitro, prevents xenogeneic GVHD, and maintains antitumor responses by cytotoxic T lymphocytes (CTLs). Aurora A/JAK2 inhibition is immunosuppressive but permits the differentiation of inducible regulatory T cells (iTregs) that are hyperfunctional and CD39 bright and efficiently scavenge adenosine triphosphate (ATP). Increased iTreg potency is primarily a function of Aurora A blockade, whereas JAK2 inhibition suppresses T helper 17 (TH17) differentiation. Inhibiting either Aurora A or JAK2 significantly suppresses TH1 T cells. However, CTL generated in vivo retains tumor-specific killing despite Aurora A/JAK2 blockade. Thus, inhibiting CD28 and IL-6 signal transduction pathways in donor T cells can increase the Treg/Tconv ratio, prevent GVHD, and preserve antitumor CTL.

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