1,721,008 research outputs found
The immunopeptidomes of two transmissible cancers and their host demonstrate a common dominant peptide motif for MHC class I molecules
No full textSource data files used for analysis of Tasmanian Devil immunopeptidome. Data files used to make Figures 1 -7 in the following paper:
Gastaldello A, Ramarathinam SH, Bailey A, Owen R, Turner S, Kontouli N, Elliott T, Skipp P, Purcell AW, Siddle HV. The immunopeptidomes of two transmissible cancers and their host demonstrate a common dominant peptide motif for MHC class I molecules. (2021)
Immunology, https://doi.org/10.1111/imm.13307</span
The differentiation state of the Schwann cell progenitor drives phenotypic variation between two contagious cancers
No full textData associated with manuscript, 'The differentiation state of the Schwann cell progenitor drives phenotypic variation between two contagious cancers'. Published in PlosPathogens
The tables below were used to generate Figures 1 -3 in the manuscript. </span
A tale of two tumours: comparison of the immune escape strategies of contagious cancers
No full textThe adaptive immune system should prevent cancer cells passing from one individual to another, in much the same way that it protects against pathogens. However, in rare cases cancer cells do not die within a single individual, but successfully pass between individuals, escaping the adaptive immune response and becoming a contagious cancer. There are two naturally occurring contagious cancers, Devil Facial Tumour Disease (DFTD), found in Tasmanian devils, and Canine Transmissible Venereal Tumour (CTVT), found in dogs. Despite sharing an ability to pass as allografts, these cancers have a very different impact on their hosts. While DFTD causes 100% mortality among infected devils and has had a devastating impact on the devil population, CTVT co-exists with its host in a manner that does not usually cause death of the dog. Although immune evasion strategies for CTVT have been defined, why DFTD is not rejected as an allograft is not understood. We have made progress in revealing mechanisms of immune evasion for DFTD both in vitro and in vivo, and here we compare how DFTD and CTVT interact with their respective hosts and avoid rejection. Our findings highlight factors that may be important for the evolution of contagious cancers and cancer more generally. Perhaps most importantly, this work has opened up important areas for future research, including the effect of epigenetic factors on immune escape mechanisms and the basis of a vaccine strategy that may protect Tasmanian devils against DFTD
Devil facial tumours: Towards a vaccine
No full textThe Tasmanian devil is the only mammalian species to harbour two independent lineages of contagious cancer. Devil facial tumour 1 (DFT1) emerged in the 1990s and has caused significant population declines. Devil facial tumour 2 (DFT2) was identified in 2014, and evidence indicates that this new tumour has emerged independently of DFT1. While DFT1 is widespread across Tasmania, DFT2 is currently found only on the Channel Peninsula in south east Tasmania. Allograft transmission of cancer cells should be prevented by major histocompatibility complex (MHC) molecules. DFT1 avoids immune detection by downregulating MHC class I expression, which can be reversed by treatment with interferon-gamma (IFNγ), while DFT2 currently circulates in hosts with a similar MHC class I genotype to the tumour. Wild Tasmanian devil numbers have not recovered from the emergence of DFT1, and it is feared that widespread transmission of DFT2 will be devastating to the remaining wild population. A preventative solution for the management of the disease is needed. Here, we review the current research on immune responses to devil facial tumours and vaccine strategies against DFT1 and outline our plans moving forward to develop a specific, effective vaccine to support the wild Tasmanian devil population against the threat of these two transmissible tumours
Characterization of major histocompatibility complex class I and class II genes from the Tasmanian devil (Sarcophilus harrisii)
No full textThe Tasmanian devil (Sarcophilus harrisii) is currently threatened by an emerging wildlife disease, devil facial tumour disease. The disease is decreasing devil numbers dramatically and may lead to the extinction of the species. At present, nothing is known about the immune genes or basic immunology of the devil. In this study, we report the construction of the first genetic library for the Tasmanian devil, a spleen cDNA library, and the isolation of full-length MHC Class I and Class II genes. We describe six unique Class II beta chain sequences from at least three loci, which belong to the marsupial Class II DA gene family. We have isolated 13 unique devil Class I sequences, representing at least seven Class I loci, two of which are most likely non-classical genes. The MHC Class I sequences from the devil have little heterogeneity, indicating recent divergence. The MHC genes described here are most likely involved in antigen presentation and are an important first step for studying MHC diversity and immune response in the devil
MHC gene copy number variation in Tasmanian devils: implications for the spread of a contagious cancer
No full textTasmanian devils face extinction owing to the emergence of a contagious cancer. Devil facial tumour disease (DFTD) is a clonal cancer spread owing to a lack of major histocompatibility complex (MHC) barriers in Tasmanian devil populations. We present a comprehensive screen of MHC diversity in devils and identify 25 MHC types and 53 novel sequences, but conclude that overall levels of MHC diversity at the sequence level are low. The majority of MHC Class I variation can be explained by allelic copy number variation with two to seven sequence variants identified per individual. MHC sequences are divided into two distinct groups based on sequence similarity. DFTD cells and most devils have sequences from both groups. Twenty per cent of individuals have a restricted MHC repertoire and contain only group I or only group II sequences. Counterintuitively, we postulate that the immune system of individuals with a restricted MHC repertoire may recognize foreign MHC antigens on the surface of the DFTD cell. The implication of these results for management of DFTD and this endangered species are discusse
Class II transactivator induces expression of MHC-I and MHC-II in transmissible Tasmanian devil facial tumours
No full textMHC-I and MHC-II molecules are critical components of antigen presentation and T cell immunity to pathogens and cancer. The two monoclonal transmissible devil facial tumours (DFT1, DFT2) exploit MHC-I pathways to overcome immunological anti-tumour and allogeneic barriers. This exploitation underpins the ongoing transmission of DFT cells across the wild Tasmanian devil population. We have previously shown that the overexpression of NLRC5 in DFT1 and DFT2 cells can regulate components of the MHC-I pathway but not MHC-II, establishing the stable upregulation of MHC-I on the cell surface. As MHC-II molecules are crucial for CD4+ T cell activation, MHC-II expression in tumour cells is beginning to gain traction in the field of immunotherapy and cancer vaccines. The overexpression of Class II transactivator in transfected DFT1 and DFT2 cells induced the transcription of several genes of the MHC-I and MHC-II pathways. This was further supported by the upregulation of MHC-I protein on DFT1 and DFT2 cells, but interestingly MHC-II protein was upregulated only in DFT1 cells. This new insight into the regulation of MHC-I and MHC-II pathways in cells that naturally overcome allogeneic barriers can inform vaccine, immunotherapy and tissue transplant strategies for human and veterinary medicine
Dataset for Doctoral Thesis, Investigating the role of MHC class I molecules in immune evasion by transmissible tumour cells
No full textDataset supporting the doctoral thesis, 'Investigating the role of MHC class I molecules in immune evasion by transmissible tumour cells' (2024)
This dataset contains:
IHC-Analysis_Macros.zip
IHC-Images.zip
NGS_Devil-Host-MHCI-Sequencing(1).zip
NGS_Devil-Host-MHCI-Sequencing(2).zip
NGS-Analysis_Scripts.zip
Tasmanian-Devil-Biopsies-Metadata.csv</span
Investigating the molecular mechanisms behind immune escape and recognition of two genetically distinct contagious cancers in the Tasmanian devil
No full textThe 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
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