PD-L1 Is Not Constitutively Expressed on Tasmanian Devil Facial Tumor Cells but Is Strongly Upregulated in Response to IFN-gamma and Can Be Expressed in the Tumor Microenvironment
- Author(s)
- Flies, AS; Lyons, AB; Corcoran, LM; Papenfuss, AT; Murphy, JM; Knowles, GW; Woods, GM; Hayball, JD;
- Journal Title
- Front Immunol
- Publication Type
- Journal Article
- Abstract
- The 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-gamma. 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.
- Publisher
- Frontiers Media
- Research Division(s)
- Molecular Immunology; Bioinformatics; Cell Signalling And Cell Death
- PubMed ID
- 28018348
- Publisher's Version
- https://doi.org/10.3389/fimmu.2016.00581
- Open Access at Publisher's Site
http://journal.frontiersin.org/article/10.3389/fimmu.2016.00581/full- NHMRC Grants
- NHMRC/1105754, NHMRC/1054925,
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2017-01-10 12:24:14
Last Modified: 2017-04-10 12:55:43