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

  • Sci Transl Med. 2017 Jan 11;9(372):eaai8269. doi: 10.1126/scitranslmed.aai8269.
Brian C Betts  1  2  3 ,  Anandharaman Veerapathran  4  2 ,  Joseph Pidala  4  2  3 ,  Hua Yang  3 ,  Pedro Horna  3  5 ,  Kelly Walton  2 ,  Christopher L Cubitt  6 ,  Steven Gunawan  3 ,  Harshani R Lawrence  3  7 ,  Nicholas J Lawrence  3  7 ,  Said M Sebti  3  7 ,  Claudio Anasetti  4  2  3
Affiliations
  • 1. Department of Blood and Marrow Transplantation, Moffitt Cancer Center, Tampa, FL 33612, USA. [email protected].
  • 2. Department of Immunology, Moffitt Cancer Center, Tampa, FL 33612, USA.
  • 3. Department of Oncologic Sciences, University of South Florida, Tampa, FL 33612, USA.
  • 4. Department of Blood and Marrow Transplantation, Moffitt Cancer Center, Tampa, FL 33612, USA.
  • 5. Department of Hematopathology and Laboratory Medicine, Moffitt Cancer Center, Tampa, FL 33612, USA.
  • 6. Translational Research Core, Moffitt Cancer Center, Tampa, FL 33612, USA.
  • 7. Department of Drug Discovery, Moffitt Cancer Center, Tampa, FL 33612, USA.
PMID: 28077684 DOI: 10.1126/scitranslmed.aai8269
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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