Written by: Padmini S. Pillai
Original Article: Caldwell et al, eLIFE 2018
The Gist of It:
Many of you may remember Taz, the beloved Tasmanian devil from The Looney Tunes Show, known for his voracious appetite and short temper. The real-life carnivorous marsupials that inspired this cartoon character are currently on the verge of extinction due to the rapid spread of a contagious cancer called Devil Facial Tumor Disease (DFTD). Recently, two different transmittable cancers have emerged in the devils, DFT1 in 1996 and DFT2 in 2014; these have resulted in the death of nearly 80% of the devil population. Tasmanian devils transmit the cancer through biting and then die from starvation as tumors grow uncontrollably on their face and mouth. Normally, cancers are not contagious because the immune system is able to distinguish foreign (non-self) cells from cells that belong within the body, using a molecule called major histocompatibility complex class I (MHC-I). T cells in the immune system recognize non-self MHC-I molecules on cells that don’t belong and destroy them. The process of identifying non-self MHC-I can protect us from bacteria and viruses, but it can also lead to organ transplant rejection. DFT1 cancer cells escape recognition by the Tasmanian devil immune system by simply not expressing MHC-I molecules on their surface. Without the non-self MHC-I, the body can’t identify that the cancer cells don’t belong. Until recently, it wasn’t clear whether the same was true for DFT2. A paper by Caldwell and colleagues used cells collected from tumors and cancer cells grown in the lab to explain how DFT2 spreads. Unlike DFT1, DFT2 cells still have MHC-I on their surface, but they express an MHC-I molecule that is genetically similar to those expressed in most Tasmanian devils. This allows the cancer cells to spread through the devil population without any T cells recognizing them as foreign. To make matters worse, analyses of tumors from many Tasmanian devils show that some DFT2 cancers are also beginning to lose their MHC-I, just like DFT1! This study gives us a close look at how contagious cancers can evolve rapidly, especially in endangered populations. Further research on how contagious cancers avoid recognition by our immune system could not only help save the Tasmanian devils, but could potentially shed light on ways to prevent transplant rejection.
DFT2 cancer cells escape elimination by immune cells by expressing an MHC-I molecule on their surface that is not recognized as foreign by the Tasmanian devil immune system.
The Nitty Gritty:
DFT2 cells were grown in culture and analyzed by flow cytometry to demonstrate expression of beta-2 microglobulin (β2M), a component of the MHC-I molecule. Quantification by RT-qPCR revealed that DFT2 cells expressed both classical and non-classical MHC-I heavy chain genes. Antibodies against classical and non-classical MHC-I heavy chains were generated and used to analyze expression of MHC-I in sections from primary DFT2 tumors. Staining revealed that surface expression of MHC-I in tumors is quite variable. Staining for CD3+ cells revealed that lymphocytic infiltration does occur in DFT2 tumors. Different DFT2 clones were found to express each of the five devil genomic MHC-I sequences, including some expressed by interferon gamma-simulated DFT1 tumor cells. Additionally, analysis of splenic mRNA samples from infected devils showed sequence similarity between MHC-I alleles expressed in three different hosts.