Doherty Institute - Theses

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    The role of CD8+ tissue-resident memory T cells in melanoma immune surveillance.
    Park, Simone Louise ( 2018)
    In addition to its role in protecting the body from infection, the immune system can prevent the development of cancer in a process termed tumour immune surveillance. During this process, immune cells can either recognise and completely eliminate cancerous cells, or can suppress the outgrowth of malignant cells without completely eradicating them. This latter mode of control, designated ‘cancer-immune equilibrium’, can be sustained for extended periods of time in a manner dependent upon adaptive immune cells such as T cells. The vast majority of human cancers are spawned from epithelial tissues. However, long-lived CD8+ circulating memory T (TCIRC) cells such as effector memory T (TEM) cells and central memory T (TCM) cells are typically excluded from epithelial tissue compartments in the absence of robust inflammation. In contrast, CD8+ tissue-resident memory T (TRM) cells are a population of non-migratory immune cells that permanently occupy epithelial tissue sites without recirculating. CD8+ TRM cells provide efficacious protection against peripheral viral and bacterial infections and have recently been identified in a variety of human solid tumours, where they associate with improved disease outcome. However, a direct role for TRM cells in promoting natural immunity to cancer has yet to be demonstrated. In this thesis, we examined the contribution of CD8+ TRM cells to peripheral cancer immune surveillance and the mechanisms through which these cells protect against tumour progression. In order to study the peripherally localised anti-tumour immune response, we developed and characterised an orthotopic epicutaneous (e.c.) model of melanoma in mice that targets tumour growth to the outermost layers of skin. We found that a portion of mice receiving tumour cells e.c. remained free of macroscopic cancer long after inoculation, in a manner that depended upon immune cell mediated control. Spontaneous protection from progressive tumour development was associated with the formation of melanoma-specific CD69+CD103+ CD8+ skin TRM cells, whereas mice genetically deficient in TRM cell formation were highly susceptible to tumour growth. Importantly, tumour-specific skin TRM cells could protect against tumour development independently of TCIRC cells. Closer inspection of macroscopically tumour-free mice revealed that many harboured occult melanoma cells in their skin long after e.c. inoculation. These dormant melanoma cells were retained in the epidermis, where they were dynamically surveyed by tumour-primed CD8+ skin TRM cells. Ablation of skin TRM cells from macroscopically tumour-free mice that were initially protected from tumour development triggered late-stage tumour outgrowth, demonstrating that CD8+ TRM cells can suppress cancer progression by promoting a state of subclinical cancer-immune equilibrium. Further, our findings suggest that the cytokine tumour necrosis factor (TNF) may play a role in the induction and maintenance of this equilibrium state. Overall, we show that CD8+ TRM cells contribute to immune surveillance of peripherally localised cancers by upholding tumour-immune equilibrium. As such, our findings elucidate how cancers arising in epithelial compartments are subject to long-term and ongoing immune suppression. Collectively, our work provides critical insight and the impetus necessary to exploit CD8+ TRM cells as targets of cancer immunotherapies in order to improve solid cancer treatments in patients.