The lymphatic vasculature is a key player in progression of many cancers, with lymphangiogenesis at the primary tumour and tumour-draining lymph nodes (TDLNs) associated with poor patient prognosis. As well as providing a highway for metastatic tumour cells, recent reports propose lymphatics as modulators of immunity, highlighting a need for greater understanding of immune regulation by lymphatics. The specific role of lymphatic endothelial cells (LECs) in this context, particularly in TDLNs, is unknown. As TDLNs are immune hubs, yet anti-tumour immune responses are often ineffective, this thesis aimed to investigate functional changes to lymphatics in TDLNs and the role of TDLN-derived LECs in anti-tumour immunity. I hypothesised that factors from the tumour microenvironment alter functionality of TDLN-LECs from early stages of tumour development. I further hypothesised that these changes would promote immune tolerance, with this thesis exploring specific impact on dendritic cell (DC) mediated immunity. Using the B16-F10 melanoma model, this work confirmed expansion of TDLN-LECs prior to metastasis and demonstrated transcriptional reprogramming of immune-associated pathways in LECs isolated from early TDLNs. This was accompanied by differentially localized migratory DCs, clustered at lymphatic subcapsular sinuses. In vitro using co-culture assays revealed mature DCs undergo prolonged interactions with LECs conditioned with B16-F10 tumour-conditioned media, suggesting a change in the physical interactions occurring in vivo in early TDLNs. Additionally, we investigated possible mechanistic contributors, demonstrating using in vitro and in vivo blockade and knockout models, a role for lymphatic expressed Podoplanin in DC interactions and migration. Prolonged physical interactions were further found to facilitate antigen transfer from ovalbumin-loaded LECs to DCs yet inhibit DC priming of T-cells, with DCs found capable of acquiring TDLN-LEC archived antigen in vivo. These results show that in lymph nodes conditioned by factors derived from the tumour microenvironment, prolonged physical interactions between LECs and DCs impact DC migration and T-cell priming. As immune tolerance is a key feature of the tumour microenvironment, this work has highlighted lymphatics as key modulators of the anti-tumour immune response. Furthermore, this work provides new insight into lymphatic involvement during tumour development, identifying lymphatics as a potential target for early intervention therapies.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:763842 |
| Date | January 2019 |
| Creators | Harris, Jennifer Nicole |
| Contributors | Shields, Jacqueline |
| Publisher | University of Cambridge |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://www.repository.cam.ac.uk/handle/1810/287480 |
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