Modulation of Immune Checkpoints and Graft-versus-Leukemia in Allogeneic Transplants by Antagonizing Vasoactive Intestinal Peptide Signaling

• Type of Material: Article
• Authors: Jian-Ming Li, Emory University; Christopher T. Petersen, Emory University; Jing-Xia Li, Central South University; Christopher T. Panjwani, Emory University; Reema Chandra, Emory University; Daniel J Giver, Emory University; Cynthia R Giver, Emory University; Bruce R. Blazar, University of Minnesota
• Language: English
• Date: 2016-12-01
• Publisher: American Association for Cancer Research
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: ©2016 AACR.
• Final Published Version (URL): http://dx.doi.org/10.1158/0008-5472.CAN-16-0427
• Title of Journal or Parent Work: Cancer Research
• ISSN: 0008-5472
• Volume: 76
• Issue: 23
• Start Page: 6802
• End Page: 6815
• Grant/Funding Information: This work was supported by Katz and WES Foundations, Winship Cancer Institute BMT Leukemia Fund, and NIH grants R01CA74364 (E.K. Waller) and R01CA72669 (B.R. Blazar)
• Keywords: CYCLASE-ACTIVATING POLYPEPTIDE; IN-VIVO; HOST-DISEASE; PLASMACYTOID DENDRITIC CELLS; ANTIVIRAL IMMUNITY; Oncology; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; Science & Technology; Life Sciences & Biomedicine; CHEMOKINE RECEPTORS; REGULATORY T-CELLS; BONE-MARROW; STEM-CELL TRANSPLANTATION
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, Immunology

Abstract

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-versushost 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.