The newly-arisen Devil facial tumour disease 2 (DFT2) reveals a mechanism for the emergence of a contagious cancer

Abstract

Devil Facial Tumour 2 (DFT2) is a recently discovered contagious cancer circulating in the Tasmanian devil (Sarcophilus harrisii), a species which already harbours a more widespread contagious cancer, Devil Facial Tumour 1 (DFT1). Here we show that in contrast to DFT1, DFT2 cells express major histocompatibility complex (MHC) class I molecules, demonstrating that loss of MHC is not necessary for the emergence of a contagious cancer. However, the most highly expressed MHC class I alleles in DFT2 cells are common among host devils or non-polymorphic, reducing immunogenicity in a population sharing these alleles. In parallel, MHC class I loss is emerging in vivo, thus DFT2 may be mimicking the evolutionary trajectory of DFT1. Based on these results we propose that contagious cancers may exploit partial histocompatibility between the tumour and host, but that loss of allogeneic antigens could facilitate widespread transmission of DFT2.

Passage of transmissible cancers in the Tasmanian devil is due to a dominant, shared peptide motif and a limited repertoire of MHC-I allotypes

“…At a minimum, we predict that fibroblasts have six allotypes at the cell surface and DFT1+IFNg and DFT2 have 3 and 5 functional allotypes respectively. These alleles correlate well with our previous definition of the MHC-I transcripts expressed by DFT1+IFNg and DFT2 and fibroblasts(1). However, there are a number of exceptions.…”

“…However, rare instances of spontaneous DFT1 tumour regression have been described and vaccination and immunotherapy of devils with live MHC-I positive DFT1 cells demonstrate that devils can mount an effective immune response against the disease in some instances (19)(20)(21). We have 5 recently shown that in contrast to DFT1, DFT2 cells express MHC-I molecules, but the expressed alleles are similar between hosts and tumours in the samples analysed (1).…”

“…Three Tasmanian devil cell lines were analysed, the devil fibroblast cell line 'Salem' (refered to as Fibroblasts in text), the DFT1-derived cell line 4906 and the DFT2-derived cell line RV (red velvet, refered to as DFT2), and are described in (1,4,41). To stimulate expression of MHC-I molecules in DFT1, cells were cultured (17 h) in medium containing recombinant devil IFNγ according to previously described protocols (18), and are refered to as DFT1+IFNg in the text.…”

Tracing the rise of malignant cell lines: Distribution, epidemiology and evolutionary interactions of two transmissible cancers in Tasmanian devils

“…We acknowledge that a larger sampling effort in areas north of the peninsula is necessary to firmly conclude that DFT2 has not escaped the confinement Another plausible explanation is the difference in MHC class I expression between both tumours. There is evidence that DFT2 cells express classical and non-classical MHC alleles, which is likely to lessen the immunogenicity of tumour cells and reduce susceptibility infection (Caldwell et al, 2018). However, the expression of MHC molecules in DFT2 is not uniform and, given its early stage of evolutionary history, is possible that it might be gradually lost, facilitating a possibly higher rate of transmission.…”

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

“…These studies have revealed that the DFT1 cells downregulate MHC class I (MHC-I) expression 19 , a phenomenon observed in many human cancers 20 . In contrast to DFT1 cells, the DFT2 cells do express MHC-I 21 . DFT1 and DFT2 cells also have 2,884 and 3,591 single nucleotide variants, respectively, that are not present in 46 normal devil genomes 22 .…”