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The role of tissue-resident memory T cells in cutaneous metastatic melanoma

Winter, Samantha (2014) The role of tissue-resident memory T cells in cutaneous metastatic melanoma. Honours thesis, Murdoch University.

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Metastatic melanoma is a highly aggressive form of cancer, with poor prognosis when diagnosed during late stages. Modern cancer immunotherapies that exploit the immune system were praised as the science ‘breakthrough of the year’ in 2013 and are exhibiting improved outcomes in the treatment of advanced melanoma. Two of these immunotherapies currently approved for clinical use are known as anti-CTLA-4 and anti-PD-1, which respectively target the cell surface markers CTLA-4 and PD-1 on CD8 T cells. CD8 T cell subsets play a superior role in inflammation and have the ability to destroy cancer cells. Following resolution of inflammation, a small number of CD8 T cells contract to form a stable pool of memory T cells. These memory CD8 T cells have the ability to mount a faster and stronger immune response compared to their short-lived predecessors. Due to their superior function and the immunogenicity of melanoma, these memory CD8 T cells play a pivotal role in the development of successful immunotherapeutic treatments. Recently, a subset of non-migratory memory CD8 T cells that reside at peripheral sites has been described, known as tissue-resident memory T cells (TRM). TRM cells are found primarily at barrier sites, such as the epidermis of the skin. Current research surrounding TRM cells has centred primarily on their role in viral infections. This project explores the presence and phenotype of TRM cells at the site of cutaneous murine melanoma. A novel model of melanoma engraftment was utilised that resembles the human disease with increased accuracy due to epidermal/dermal infiltration, which is not seen in traditional murine melanoma models. TRM cells were
able to be identified, enumerated and phenotyped at different stages of tumour control, by designing a protocol which employed cutaneous melanoma, traceable tumour-specific gBT.I CD8 T cells and HSV-1 infection. TRM cells were found to be present at the site of tumour at numbers similar to unmanipulated control skin. In contrast, elevated numbers were seen in HSV-1 infected skin. At the site of cutaneous melanoma, TRM cells were found to have a KLRG1lo, CTLA-4hi and PD-1lo phenotype at each time point analysed, identical to TRM cells isolated from control and HSV-1 infected skin. These findings suggest the need for further research into TRM cell function during immunotherapy, as expression of CTLA-4 and PD-1 surface markers render TRM cells as potential targets for anti-CTLA-4 and anti-PD-1 monoclonal antibody treatment.

Item Type: Thesis (Honours)
Murdoch Affiliation(s): School of Veterinary and Life Sciences
Supervisor(s): Waithman, J., Mead, Robert, Gebhardt, Thomas and Endersby, Raelene
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