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Author Notes:

Corresponding author: Edmund K. Waller, MD, PhD, 1365B Clifton Road NE, Winship Cancer Institute, Emory University, Atlanta, GA 30322, ewaller@emory.edu Phone: 404-727-4995, Fax: 404-778-5530

Conception and design: J.-M. Li, C.T. Petersen, B.R. Blazar, E.K. Waller

Development of methodology: J.-M. Li, E.K. Waller

Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): J.-M. Li, C.T. Petersen, J.-X. Li, R. Panjwani, C.R. Giver, B.R. Blazar, E.K. Waller

Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): J.-M. Li, C.T. Petersen, J.-X. Li, R. Panjwani, B.R. Blazar, E.K. Waller

Writing, review, and/or revision of the manuscript: J.-M. Li, C.T. Petersen, J.-X. Li, R. Panjwani, D.J. Chandra, C.R. Giver, B.R. Blazar, E.K. Waller

Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): J.-M. Li, D.J. Chandra, E.K. Waller

Study supervision: J.-M. Li, E.K. Waller

The authors thank Wayne Harris and Pabu Devadas for technical assistance.

No potential conflicts of interest were disclosed.

Subjects:

Research Funding:

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:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Oncology
  • EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS
  • STEM-CELL TRANSPLANTATION
  • CYCLASE-ACTIVATING POLYPEPTIDE
  • PLASMACYTOID DENDRITIC CELLS
  • REGULATORY T-CELLS
  • HOST-DISEASE
  • CHEMOKINE RECEPTORS
  • BONE-MARROW
  • ANTIVIRAL IMMUNITY
  • IN-VIVO

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

Tools:

Journal Title:

Cancer Research

Volume:

Volume 76, Number 23

Publisher:

, Pages 6802-6815

Type of Work:

Article | Post-print: After Peer Review

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.

Copyright information:

©2016 AACR.

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