A novel system to map protein interactions reveals evolutionarily conserved immune evasion pathways on transmissible cancers

Around 40% of humans and captive Tasmanian devils (Sarcophilus harrisii) develop cancer, compared to less than 10% for most species. Tasmanian devils also suffer from two of the three known naturally-occurring transmissible cancers detected in vertebrate species. Transmissible cancers are a unique form of cancer in which tumor cells act as an infectious pathogen and an allograft. The two different transmissible devil facial tumors (DFT1 and DFT2) overcome immunological barriers (e.g. major histocompatibility complex) and have killed thousands of devils. Immune checkpoint immunotherapy has revolutionized human oncology in recent years. However, immune checkpoints in transmissible and non-transmissible cancers remains largely unexplored in most species due to a lack of species-specific reagents. To overcome this, we developed a “cut-and-paste” Fluorescent Adaptable Simple Theranostic (FAST) protein system, adaptable for any vertebrate species. This method facilitated rapid confirmation of seven receptor-ligand interactions between twelve immune checkpoint proteins in Tasmanian devils, thus filling a 160 million year gap in our understanding of the evolution of the mammalian immune system. We used this system to investigate the checkpoint molecule CD200, which can inhibit natural killer cell responses to cancer and facilitate graft tolerance in humans and mice. CD200 was highly expressed on DFT cells and can be used to identify DFT cells in devil blood. Understanding how transmissible tumor cells graft onto new hosts and evade immune defenses will help to identify evolutionarily conserved immunological principles relevant to transplant immunology, cancer, and infectious disease for human and veterinary medicine.