Immune recognition of transmissible cancers in Tasmanian devils with MHC-I deletion

Devil facial tumour disease (DFTD), caused by transmissible cancers, has decimated the wild Tasmanian devil (Sarcophilus harrisii) population. Devil facial tumour 1 (DFT1) cancer cells have spread due to low major histocompatibility complex class I (MHC-I) diversity in the species, as well as epigenetic regulation of MHC-I proteins on DFT1 cells to evade allograft responses. Tumour regression, recovery from disease, and immune recognition of DFT1 cells have been documented in a small number of cases. Here we tested the hypothesis that antibody response to DFT1 was associated with dissimilarity of host and tumour MHC-I types. We found that most individuals with antibodies against DFT1 cells do not share any alleles with DFT1 at the MHC-I UA locus. In addition to allelic mismatches, deletion of the UA locus increases the likelihood of immune response against DFT1 cells. Strikingly, we show that loss of the UA locus is being selected for at long-term disease sites. We conclude that deletion of an entire MHC locus provides some protection against DFT1. However, not all individuals that generate antibody responses are protected from DFT1, and loss of UA is not sufficient to ensure survival. Our study provides the first evidence of a complete gene loss in a species in response to a disease threat. Further evolutionary loss of MHC-I diversity will increase the species risk of future disease epidemics and further jeopardise the long-term viability of the species. Significance StatementTasmanian devil populations have been decimated by devil facial tumour 1, an infectious cancer that spreads due to low major histocompatibility complex class I (MHC-I) diversity. We show that a deletion of the UA locus increases the likelihood of immune response against DFT1 cells and conclude that the loss of an entire MHC locus provides some protection against DFT1 and show that it is increasing in frequency in long-term diseased sites. This is the first evidence of a complete gene loss in a species response to a disease threat, but we caution that loss of MHC-I diversity in devils will increase their risk of extinction due to further loss of genetic resilience.