Flies Andrew S, Lyons A Bruce, Corcoran Lynn M, Papenfuss Anthony T, Murphy James M, Knowles Graeme W, Woods Gregory M, Hayball John D
Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia; Experimental Therapeutics Laboratory, Hanson Institute, School of Pharmacy and Medical Science, University of South Australia, Adelaide, SA, Australia; Experimental Therapeutics Laboratory, Sansom Institute, School of Pharmacy and Medical Science, University of South Australia, Adelaide, SA, Australia.
School of Medicine, University of Tasmania , Hobart, TAS , Australia.
Front Immunol. 2016 Dec 9;7:581. doi: 10.3389/fimmu.2016.00581. eCollection 2016.
The devil facial tumor disease (DFTD) is caused by clonal transmissible cancers that have led to a catastrophic decline in the wild Tasmanian devil () 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, 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.
袋獾面部肿瘤病（DFTD）由克隆性可传播癌症引起，导致野生塔斯马尼亚袋獾（）种群数量灾难性下降。首个可传播肿瘤，现称为袋獾面部肿瘤1型（DFT1），于1996年首次发现，并已持续传播至新宿主至少20年。2015年，在野生袋獾中发现了第二种可传播癌症[袋獾面部肿瘤2型（DFT2）]，DFT2在基因上与DFT1不同且独立。尽管与两个正常袋獾参考基因组相比，DFT1基因组估计有136559个碱基对替换和14647个插入/缺失，但同种异体移植肿瘤并未被宿主免疫系统排斥。此外，对DFT1两个亚株的基因组测序检测到超过15000个单碱基替换，这些替换仅在其中一个DFT1亚株中发现，表明可传播肿瘤在不断进化，新抗原的产生可能正在进行。人类临床试验的最新证据表明，阻断PD-1:PD-L1相互作用可促进抗肿瘤免疫反应，并且在具有大量突变的癌症中最为有效。我们推测DFTD细胞可能利用PD-1:PD-L1抑制途径逃避抗肿瘤免疫反应。我们开发了重组蛋白和单克隆抗体（mAb），首次证明在非胎盘哺乳动物中PD-1与PD-L1和PD-L2均结合，并表明DFTD细胞中PD-L1在干扰素-γ刺激下上调。免疫组织化学显示，PD-L1在原发性肿瘤块中很少表达，但在一些转移性肿瘤的微环境中检测到少量PD-L1非肿瘤细胞。重要的是，检测表明mAb可阻断PD-1与PD-L1和PD-L2的结合，这对于理解DFT同种异体移植如何逃避免疫系统可能至关重要。
