Please use this identifier to cite or link to this item: https://hdl.handle.net/2440/111032
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Type: Journal article
Title: Comparative analysis of immune checkpoint molecules and their potential role in the transmissible Tasmanian Devil facial tumor disease
Author: Flies, A.
Blackburn, N.
Lyons, A.
Hayball, J.
Woods, G.
Citation: Frontiers in Immunology, 2017; 8(MAY):513-1-513-27
Publisher: Frontiers Media
Issue Date: 2017
ISSN: 1664-3224
1664-3224
Statement of
Responsibility: 
Andrew S. Flies, Nicholas B. Blackburn, Alan Bruce Lyons, John D. Hayball and Gregory M. Woods
Abstract: Immune checkpoint molecules function as a system of checks and balances that enhance or inhibit immune responses to infectious agents, foreign tissues, and cancerous cells. Immunotherapies that target immune checkpoint molecules, particularly the inhibitory molecules programmed cell death 1 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), have revolutionized human oncology in recent years, yet little is known about these key immune signaling molecules in species other than primates and rodents. The Tasmanian devil facial tumor disease is caused by transmissible cancers that have resulted in a massive decline in the wild Tasmanian devil population. We have recently demonstrated that the inhibitory checkpoint molecule PD-L1 is upregulated on Tasmanian devil (Sarcophilus harrisii) facial tumor cells in response to the interferon-gamma cytokine. As this could play a role in immune evasion by tumor cells, we performed a thorough comparative analysis of checkpoint molecule protein sequences among Tasmanian devils and eight other species. We report that many of the key signaling motifs and ligand-binding sites in the checkpoint molecules are highly conserved across the estimated 162 million years of evolution since the last common ancestor of placental and non-placental mammals. Specifically, we discovered that the CTLA-4 (MYPPPY) ligand-binding motif and the CTLA-4 (GVYVKM) inhibitory domain are completely conserved across all nine species used in our comparative analysis, suggesting that the function of CTLA-4 is likely conserved in these species. We also found that cysteine residues for intra- and intermolecular disulfide bonds were also highly conserved. For instance, all 20 cysteine residues involved in disulfide bonds in the human 4-1BB molecule were also present in devil 4-1BB. Although many key sequences were conserved, we have also identified immunoreceptor tyrosine-based inhibitory motifs (ITIMs) and immunoreceptor tyrosine-based switch motifs (ITSMs) in genes and protein domains that have not been previously reported in any species. This checkpoint molecule analysis and review of salient features for each of the molecules presented here can serve as road map for the development of a Tasmanian devil facial tumor disease immunotherapy. Finally, the strategies can be used as a guide for veterinarians, ecologists, and other researchers willing to venture into the nascent field of wild immunology.
Keywords: Devil, transmissible tumor; cosignaling immunotherapy; checkpoint blockade; wild immunity; allograft; transplant rejection; evolution
Rights: Copyright © 2017 Flies, Blackburn, Lyons, Hayball and Woods. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
DOI: 10.3389/fimmu.2017.00513
Grant ID: http://purl.org/au-research/grants/arc/LP0989727
http://purl.org/au-research/grants/arc/DP130100715
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