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    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

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    Author
    Flies, AS; Lyons, AB; Corcoran, LM; Papenfuss, AT; Murphy, JM; Knowles, GW; Woods, GM; Hayball, JD
    Date
    2016-12-09
    Source Title
    Frontiers in Immunology
    Publisher
    FRONTIERS MEDIA SA
    University of Melbourne Author/s
    Murphy, James; Corcoran, Lynn; Papenfuss, Anthony
    Affiliation
    Medical Biology (W.E.H.I.)
    Metadata
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    Document Type
    Journal Article
    Citations
    Flies, A. S., Lyons, A. B., Corcoran, L. M., Papenfuss, A. T., Murphy, J. M., Knowles, G. W., Woods, G. M. & Hayball, J. D. (2016). 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. FRONTIERS IN IMMUNOLOGY, 7 (DEC), https://doi.org/10.3389/fimmu.2016.00581.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/257817
    DOI
    10.3389/fimmu.2016.00581
    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-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.

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