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Title: Investigating the molecular mechanisms behind immune escape and recognition of two genetically distinct contagious cancers in the Tasmanian devil
Author: Caldwell, Alison
ISNI:       0000 0004 7234 294X
Awarding Body: University of Southampton
Current Institution: University of Southampton
Date of Award: 2018
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The Tasmanian devil (Sarcophilus harrisii), a marsupial species endemic to the island of Tasmania, harbours two distinct contagious cancers, Devil Facial Tumour 1 (DFT1) and Devil Facial Tumour 2 (DFT2) that arose in two different individuals before transmitting through the population. The tumour cells pass between individuals, seeding the growth of large tumours around the face of affected animals. While these cancers are rare, a contagious cancer also exists in dogs and five contagious cancers circulate in bivalves. The ability of tumour cells to transmit between individuals is surprising since these cells are an allograft and should not be able to pass major histocompatibility barriers. Previous work from our lab has demonstrated that this is due to down-regulation of MHC class I molecules on the surface of DFT1 cells and that this is a result of DFT1 cells only exhibiting trace levels of β2m, TAP1 and TAP2 transcripts. In addition treatment of DFT1 cells with the inflammatory cytokine IFNγ restores MHC class I expression in vitro and in some rare cases DFT1 cells do express MHC class I on their cell surface. However, this does not stimulate a full successful immune response. Here I 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 repertoire of expressed MHC class I is limited and skewed in favour of a non-polymorphic, non-classical MHC class I molecule. Further, I show that DFT1 cells can in fact express MHC class I in vivo and this corresponds with expression of immune infiltrates. Both DFT1 and DFT2 tumours show heterogeneity and MHC class I varies between and within DFT1 and DFT2 tumour samples. I show that both classical and non-classical MHC class I are upregulated in IFNγ treated DFT1 cells. Finally, infected hosts of DFT2 share at least three MHC class I transcripts with DFT2 cells, indicating that DFT2 may be confined to individuals with a particular genotype and the MHC class I expressed by DFT1 and DFT2 are closely matched, which may represent an advantageous MHC repertoire for the emergence of contagious cancer.
Supervisor: Siddle, Hannah Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available