Modulation of Immune Checkpoints and Graft-versus-Leukemia in Allogeneic Transplants by Antagonizing Vasoactive Intestinal Peptide Signaling.
The goal of allogeneic bone marrow transplantation (allo-BMT) is elimination of leukemia cells through the graft-versus-leukemia (GvL) activity of donor cells, while limiting graft-versus-host disease (GvHD). Immune checkpoint pathways regulate GvL and GvHD activities, but blocking antibodies or genetic inactivation of these pathways can cause lethal GVHD. Vasoactive intestinal peptide (VIP) is an immunosuppressive neuropeptide that regulates coinhibitory pathways; its role in allo-BMT has not been studied. We found VIP transiently expressed in donor NK, NK-T, dendritic cells, and T cells after allo transplant, as well as host leukocytes. A peptide antagonist of VIP signaling (VIPhyb) increased T-cell proliferation in vitro and reduced IL10 expression in donor T cells. Treatment of allo-BMT recipients with VIPhyb, or transplanting donor grafts lacking VIP (VIP-KO), activated donor T-cells in lymphoid organs, reduced T-cell homing to GvHD target organs, and enhanced GvL without increasing GvHD in multiple allo-BMT models. Genetic or ex vivo depletion of donor NK cells or CD8+T cells from allografts abrogated the VIPhyb-enhanced GvL activity. VIPhyb treatment led to downregulation of PD-1 and PD-L1 expression on donor immune cells, increased effector molecule expression, and expanded oligoclonal CD8+T cells that protected secondary allo transplant recipients from leukemia. Blocking VIP signaling thus represents a novel pharmacologic approach to separate GvL from GvHD and enhance adaptive T-cell responses to leukemia-associated antigens in allo-BMT. Cancer Res; 76(23); 6802-15. ©2016 AACR.
Department of Hematology/Oncology, Emory University, Atlanta, Georgia.
Jian-Ming
JM
Li
Department of Hematology/Oncology, Emory University, Atlanta, Georgia.
Christopher T
CT
Petersen
Department of Hematology/Oncology, Emory University, Atlanta, Georgia.|Department of Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, China.
Jing-Xia
JX
Li
Department of Hematology/Oncology, Emory University, Atlanta, Georgia.
Reema
R
Panjwani
Department of Hematology/Oncology, Emory University, Atlanta, Georgia.
Daniel J
DJ
Chandra
Department of Hematology/Oncology, Emory University, Atlanta, Georgia.
Cynthia R
CR
Giver
Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota.
Bruce R
BR
Blazar
Department of Hematology/Oncology, Emory University, Atlanta, Georgia. ewaller@emory.edu.
Edmund K
EK
Waller
D000818:Animals; D016026:Bone Marrow Transplantation / Q000379:methods*; D020544:Graft vs Leukemia Effect / Q000276:immunology*; D006801:Humans; D008297:Male; D051379:Mice; D015398:Signal Transduction; D019172:Transplantation Conditioning / Q000379:methods*; D014184:Transplantation, Homologous / Q000379:methods*; D014660:Vasoactive Intestinal Peptide / Q000378:metabolism*
D014660:Vasoactive Intestinal Peptide
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