Meeting Abstract
Blocking binding between PD-1 and its co-receptors B7-H1 (PD-L1) and B7-DC (PD-L2) has yielded durable responses against several types of late stage melanoma, lung, and renal cancers in humans. Recent evidence suggests that blocking PD-1:B7-H1 signalling promotes anti-tumour responses by releasing pre-existing CD8 T cells from inhibitory signalling between PD-1 and B7-H1, and that blocking the PD-1 pathway is most effective in cancers with a high number of mutations. The Tasmanian devil facial tumor (DFTD) is a clonal, transmissible tumor that was first discovered in the wild in 1996 and the DFTD is the primary cause of a greater than 85% decline in the wild Tasmanian devil population. In the nearly 20 years of ongoing transmission the tumor has accumulated greater than 17,000 somatic mutations, and a tetraploid strain of the tumor has been discovered in the wild. We hypothesize that the tumor uses inhibitory co-signalling molecules to evade the immune system, and that an anti-tumor immune response can be induced by blocking inhibitory signalling through PD-1. We have developed a panel of devil specific α-PD-1 and α-B7-H1 monoclonal antibodies (mAbs) that are capable of blocking PD-1 from binding to B7-H1 and B7-DC. We have found that PD-1 and B7-H1 are expressed in devil lymph nodes, with PD-1 being expressed primarily in germinal centers. We are currently investigating expression of B7-H1 in tumor cells and the tumor microenvironment. We have previously show that the DFT cells do not express MHC, but MHC can be induced via IFNγ. However, B7-H1 is also upregulated by the tumor in response to IFNγ treatment, suggesting that blocking B7-H1 in the tumor microenvironment might be critical to the development of the DFTD vaccine.
