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

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 (iT_regs) that are hyperfunctional and CD39 bright and eff

SUBMITTER: Betts BC 

PROVIDER: S-EPMC6368389 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature