A novel screen to understand preDC migration and improve recruitment to the tumour microenvironment

Shergold, Amy Lee (2024) A novel screen to understand preDC migration and improve recruitment to the tumour microenvironment. PhD thesis, University of Glasgow.

Abstract

Classical dendritic cells (cDCs) are a rare, but vital, component of the tumour microenvironment (TME). Their presence improves prognosis and response to current immunotherapies. Although therapeutics have been developed to increase cDC development, and thus their abundance in the tumour, we aimed to understand if cDCs could be induced to specifically infiltrate the TME instead of increasing their numbers systemically. Thus, we set out to investigate if tissue specific signals were involved in the recruitment of cDC precursors.

Precursors of cDC (preDCs) are a heterogeneous group that differentiate in the bone marrow. In the periphery, pre-cDC1s develop into cDC1s and pre-cDC2 into cDC2s, respectively. To infiltrate these tissues, preDCs must migrate through the blood to peripheral tissues but the signals controlling tissue recruitment are unknown, including whether both subsets respond to common factors and if there exist tissue-specific controls. Understanding preDC recruitment will allow us to understand cDC development as well as exploit means to manipulate their seeding in the periphery. This manipulation has the potential to improve cDC infiltration in the tumour microenvironment with potential therapeutic benefit.

Here we present evidence that preDC subsets express distinct chemokine receptors and respond to different chemokine signals in the TME. Additionally, we provide a universal assay that can be used to measure the migration of all immune cells that arise from haematopoiesis to all peripheral tissues and during multiple contexts. With this assay we have unpicked which chemokine receptors are involved in the tissue specific seeding of preDCs peripherally, including subcutaneous tumours.

Thus, this project has contributed to the knowledge of how cDC infiltration is controlled and identified means to exploit their migration patterns.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Supervisor's Name: Roberts, Dr. Ed
• Date of Award: 2024
• Depositing User: Theses Team
• Unique ID: glathesis:2024-84097
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 22 Feb 2024 09:45
• Last Modified: 22 Feb 2024 12:55
• Thesis DOI: 10.5525/gla.thesis.84097
• URI: https://theses.gla.ac.uk/id/eprint/84097