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

Brian C. Betts, Anandharaman Veerapathran, Joseph Pidala, Hua Yang, Pedro Horna, Kelly Walton, Christopher L. Cubitt, Steven Gunawan, Harshani R. Lawrence, Nicholas J. Lawrence, Said M. Sebti, Claudio Anasetti

Research output: Contribution to journalArticle

16 Scopus citations

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.

Original languageEnglish (US)
Article numbereaai8269
JournalScience translational medicine
Volume9
Issue number372
DOIs
StatePublished - Jan 11 2017
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

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    Betts, B. C., Veerapathran, A., Pidala, J., Yang, H., Horna, P., Walton, K., Cubitt, C. L., Gunawan, S., Lawrence, H. R., Lawrence, N. J., Sebti, S. M., & Anasetti, C. (2017). Targeting Aurora kinase A and JAK2 prevents GVHD while maintaining Treg and antitumor CTL function. Science translational medicine, 9(372), [eaai8269]. https://doi.org/10.1126/scitranslmed.aai8269