title: 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 (iTregs) that are hyperfunctional and CD39 bright and efficiently scavenge adenosine triphosphate (ATP). Increased iTregpotency 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/Tconvratio, prevent GVHD, and preserve antitumor CTL.
authors.affiliation: Department of Blood and Marrow Transplantation, Moffitt Cancer Center, Tampa, FL 33612, USA. brian.betts@moffitt.org.|Department of Immunology, Moffitt Cancer Center, Tampa, FL 33612, USA.|Department of Oncologic Sciences, University of South Florida, Tampa, FL 33612, USA.
authors.forename: Brian C
authors.initials: BC
authors.lastname: Betts
authors.affiliation: Department of Blood and Marrow Transplantation, Moffitt Cancer Center, Tampa, FL 33612, USA.|Department of Immunology, Moffitt Cancer Center, Tampa, FL 33612, USA.
authors.forename: Anandharaman
authors.initials: A
authors.lastname: Veerapathran
authors.affiliation: Department of Blood and Marrow Transplantation, Moffitt Cancer Center, Tampa, FL 33612, USA.|Department of Immunology, Moffitt Cancer Center, Tampa, FL 33612, USA.|Department of Oncologic Sciences, University of South Florida, Tampa, FL 33612, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Pidala
authors.affiliation: Department of Oncologic Sciences, University of South Florida, Tampa, FL 33612, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Oncologic Sciences, University of South Florida, Tampa, FL 33612, USA.|Department of Hematopathology and Laboratory Medicine, Moffitt Cancer Center, Tampa, FL 33612, USA.
authors.forename: Pedro
authors.initials: P
authors.lastname: Horna
authors.affiliation: Department of Immunology, Moffitt Cancer Center, Tampa, FL 33612, USA.
authors.forename: Kelly
authors.initials: K
authors.lastname: Walton
authors.affiliation: Translational Research Core, Moffitt Cancer Center, Tampa, FL 33612, USA.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Cubitt
authors.affiliation: Department of Oncologic Sciences, University of South Florida, Tampa, FL 33612, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Gunawan
authors.affiliation: Department of Oncologic Sciences, University of South Florida, Tampa, FL 33612, USA.|Department of Drug Discovery, Moffitt Cancer Center, Tampa, FL 33612, USA.
authors.forename: Harshani R
authors.initials: HR
authors.lastname: Lawrence
authors.affiliation: Department of Oncologic Sciences, University of South Florida, Tampa, FL 33612, USA.|Department of Drug Discovery, Moffitt Cancer Center, Tampa, FL 33612, USA.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Lawrence
authors.affiliation: Department of Oncologic Sciences, University of South Florida, Tampa, FL 33612, USA.|Department of Drug Discovery, Moffitt Cancer Center, Tampa, FL 33612, USA.
authors.forename: Said M
authors.initials: SM
authors.lastname: Sebti
authors.affiliation: Department of Blood and Marrow Transplantation, Moffitt Cancer Center, Tampa, FL 33612, USA.|Department of Immunology, Moffitt Cancer Center, Tampa, FL 33612, USA.|Department of Oncologic Sciences, University of South Florida, Tampa, FL 33612, USA.
authors.forename: Claudio
authors.initials: C
authors.lastname: Anasetti
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001381:Azepines / Q000494:pharmacology; D018106:CD28 Antigens / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation; D005260:Female; D006086:Graft vs Host Disease / Q000517:prevention & control*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007938:Leukemia / Q000628:therapy*; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D051379:Mice; D009364:Neoplasm Recurrence, Local / Q000517:prevention & control; D009368:Neoplasm Transplantation; D011743:Pyrimidines / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology*; D058504:Th17 Cells / Q000166:cytology; D000096926:Benzenesulfonamides
chemical_list: D000970:Antineoplastic Agents; D064096:Aurora Kinase A; D001381:Azepines; D018106:CD28 Antigens; D007166:Immunosuppressive Agents; D015850:Interleukin-6; D053614:Janus Kinase 2; D011743:Pyrimidines; D011759:Pyrrolidines; D013449:Sulfonamides; C550258:MLN 8237; C528327:fedratinib; D000096926:Benzenesulfonamides; C507924:JAK2 protein, human