Modulation of Immune Checkpoints and Graft-versus-Leukemia in Allogeneic Transplants by Antagonizing Vasoactive Intestinal Peptide Signaling
Autor: | Daniel J. Chandra, Edmund K. Waller, Reema Panjwani, Jian-Ming Li, Cynthia R. Giver, Christopher T. Petersen, Bruce R. Blazar, Jing Xia Li |
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Rok vydání: | 2016 |
Předmět: |
0301 basic medicine
Male Cancer Research Transplantation Conditioning Vasoactive intestinal peptide chemical and pharmacologic phenomena Graft vs Leukemia Effect Biology Article 03 medical and health sciences Mice 0302 clinical medicine Immune system Antigen immune system diseases medicine Animals Humans Transplantation Homologous Bone Marrow Transplantation medicine.disease Immune checkpoint Transplantation Leukemia Interleukin 10 030104 developmental biology surgical procedures operative Oncology Immunology CD8 030215 immunology Signal Transduction Vasoactive Intestinal Peptide |
Zdroj: | Cancer research. 76(23) |
ISSN: | 1538-7445 |
Popis: | 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. |
Databáze: | OpenAIRE |
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