Flies et al._2016_Frontiers in Immunology_PD-L1 Is Not Constitutively Expressed on Tasmanian Devil Facial Tumor Cells but Is Strongly Up.pdf (8.71 MB)
PD-L1 is not constitutively expressed on Tasmanian devil facial tumor cells but is strongly upregulated in response to IFN-γ and can be expressed in the tumor microenvironment
journal contribution
posted on 2023-05-19, 00:36 authored by Andrew FliesAndrew Flies, Alan Lyons, Corcoran, LM, Papenfuss, AT, Murphy, JM, Knowles, GW, Gregory WoodsGregory Woods, Hayball, JDThe devil facial tumor disease (DFTD) is caused by clonal transmissible cancers that have led to a catastrophic decline in the wild Tasmanian devil (Sarcophilus harrisii) population. The first transmissible tumor, now termed devil facial tumor 1 (DFT1), was first discovered in 1996 and has been continually transmitted to new hosts for at least 20 years. In 2015, a second transmissible cancer [devil facial tumor 2 (DFT2)] was discovered in wild devils, and the DFT2 is genetically distinct and independent from the DFT1. Despite the estimated 136,559 base pair substitutions and 14,647 insertions/deletions in the DFT1 genome as compared to two normal devil reference genomes, the allograft tumors are not rejected by the host immune system. Additionally, genome sequencing of two sub-strains of DFT1 detected greater than 15,000 single-base substitutions that were found in only one of the DFT1 sub-strains, demonstrating the transmissible tumors are evolving and that generation of neoantigens is likely ongoing. Recent evidence in human clinical trials suggests that blocking PD-1:PD-L1 interactions promotes antitumor immune responses and is most effective in cancers with a high number of mutations. We hypothesized that DFTD cells could exploit the PD-1:PD-L1 inhibitory pathway to evade antitumor immune responses. We developed recombinant proteins and monoclonal antibodies (mAbs) to provide the first demonstration that PD-1 binds to both PD-L1 and PD-L2 in a non-placental mammal and show that PD-L1 is upregulated in DFTD cells in response to IFN-γ. Immunohistochemistry showed that PD-L1 is rarely expressed in primary tumor masses, but low numbers of PD-L1+ non-tumor cells were detected in the microenvironment of several metastatic tumors. Importantly, in vitro testing suggests that PD-1 binding to PD-L1 and PD-L2 can be blocked by mAbs, which could be critical to understanding how the DFT allografts evade the immune system.
Funding
University of Tasmania Foundation Inc
History
Publication title
Frontiers in ImmunologyVolume
7Article number
581Number
581Pagination
1-13ISSN
1664-3224Department/School
Menzies Institute for Medical ResearchPublisher
Frontiers Research FoundationPlace of publication
SwitzerlandRights statement
Copyright 2016 the authors. Licensed under Creative Commons Attribution 4.0 International (CC BY 4.0) https://creativecommons.org/licenses/by/4.0/ This Document is Protected by copyright and was first published by Frontiers. All rights reserved. it is reproduced with permission.Repository Status
- Open