- Title
- Characterising MAIT cells in human mucosal cancers
- Creator
- Kelly, Jason
- Date
- 2021
- Type
- Text; Thesis; PhD
- Identifier
- http://researchonline.federation.edu.au/vital/access/HandleResolver/1959.17/183604
- Identifier
- vital:16322
- Abstract
- Mucosal associated invariant T cells (MAIT cells) are MR1-restricted T cells that regulate the local immune milieu with cytotoxic and cytokine responses. MAIT cells are well-known for their antimicrobial properties but are also of interest in mucosal cancers, such as colorectal cancer (CRC) and lung cancer (LC). These cancers arise in tissues that provide a barrier to the gut-resident microbiota that can potentially stimulate MAIT cells. Previous studies established that MAIT cells are present within CRC tissues, but there has been contradictory evidence about their significance within these tumour tissues. For example, their cytokine response may promote tumour elimination; however, the high frequencies of MAIT cells within CRC correlate with poor prognostic outcomes, suggesting they may be detrimental in these cancers. Despite the interest in MAIT cells within these tumours, little is known about their location, activation status and cytokine potential within the neoplastic tissue. Chapter 1 of this project investigated human circulating MAIT cells in both CRC and LC patients, finding a significant reduction in the frequency of circulating MAIT cells in the LC patient cohort. We also investigated the frequency and location of MAIT cells within non-cancerous colorectal tissues, identifying that MAIT cells are frequent in the sub-epithelial dome of gut-associated lymphoid tissue (GALT). In contrast, MAIT cells are frequent in the inflammatory response at the tumour margin in CRC tissues. Chapter 2 of this project investigated MAIT cell activation within the CRC tumour environment, with CD25 analysis identifying that MAIT cells appeared to be selectively activated within CRC tissue. We then sought to identify which cells within CRC tissue can present the cognate MAIT cell antigen, finding that CRC cells can take up soluble antigen, upregulate MR1 to the cell surface, and activate MAIT cells. However, these experiments identified a yet to be characterised soluble product secreted by CRC cells that appears to suppress MAIT cell TNF expression after encountering antigen. Chapter 3 of this project investigated MAIT cell responses after chronic (> 2 weeks) stimulation via TCR signalling, a condition likely to be found in both CRC tissue and pre-cancerous lesions, as these lesions are associated with mucosal barrier defects that allow microbes within the gut lumen to transit the barrier. These investigations found a novel, mixed Th1/Th2 cytokine response that included prodigious IL-13 expression. We found that the IL-13 produced by chronically stimulated MAIT cells was sufficient to signal to CRC cells and induce CRC cell transcriptional changes via the STAT6 pathway. Collectively, the findings of our study have provided new insights about the significance of MAIT cells in CRC and highlighted them as a potential target for immunotherapies to improve anti-tumour immunity in mucosal tissues.; Doctor of Philosophy
- Publisher
- Federation University Australia
- Rights
- All metadata describing materials held in, or linked to, the repository is freely available under a CC0 licence
- Rights
- Copyright Jason Kelly
- Rights
- Open Access
- Subject
- MAIT cells; Colorectal Cancer; Lung Cancer
- Full Text
- Thesis Supervisor
- Berzins, Stuart
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