The Tasmanian devil facial tumor (DFT), a sort of transmissible cancer, is threatening the survival of the largest carnivorous marsupial. Right from its discovery, however, scientists suspected studying the DFT's distinctive features might help us understand human cancers. The idea is bearing fruit, with devil research expanding our knowledge of how some cancers hide from the immune system, potentially widening the scope of trials that have already started on a new class of cancer-fighting drugs.
The body's defense against threats depends heavily on T cells, which eliminate cells that have become cancerous or infected by a virus. To identify cells in need of destruction T cells rely on MHC-I proteins expressed on the cell surface. When a cell is unhealthy the proteins incorporate peptides that act as a beacon to T cells.
Dr Marian Burr of Australia's Peter MacCallum Cancer Centre noted one of the ways some cancers fly under the T cells' radar is by expressing fewer MHC-I proteins. Without the presence of the proteins, there can be no warning peptides, and the T cells leave the cancers alone.
"We think this could contribute to some cancers in people becoming resistant to immunotherapies,” Burr said in a statement.
Having identified this feature in cancers, Burr and colleagues drew on other teams' research showing DFT does something similar. Devils bite each other's faces during fighting or play, and can transmit cancer cells in the process. The lack of expression of MHC-I proteins allows the cancer cells to evade the immune system and grow in their new host until becoming lethal, instead of being recognized as invaders.
Burr told IFLScience the fact DFT operates in this way alerted her team to the MHC-I silencing being an ancient evolutionary feature, and therefore likely to be widespread among cancers, rather than restricted to those her team had been studying. It also expanded their understanding of the mechanisms through which MHC-I silencing can occur.
MHC presence is associated with high levels of PRC2 proteins in the cancers Burr studied. The genes associated with this over-activity are blocked by several classes of drugs, including EZH2 inhibitors. In Cancer Cell Burr reports using EZH2 inhibitors to block PRC2 activity, and seeing a restoration of MHC-I molecules on the cancer cells' surfaces.
EZH2 inhibitors are already in clinical trials against a number of cancers including lymphomas, having showed promise in animal trials. However, this has been inspired by different ideas about their mechanism of action.
Burr and colleagues think that by combining EZH2 treatments with immunotherapies it may be possible to deliver a double hit to cancers such as small cell lung cancers and neuroblastomas, with the drugs working directly, and also boosting immunotherapy.
Burr isn't sure how well such treatments will translate to the devils, however. She noted to IFLScience that even if treating sick devils with EZH2 in captivity proves viable, assisting the larger and more threatened wild population is likely to be far more of a challenge.