Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.713106
Title: Visualisation and monitoring of tumour-mediated immune modulation in primary cancer and premetastatic niche establishment using S100A8/A9-specific imaging
Author: Eisenblaetter, Michel
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2017
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Abstract:
Development and spread of malignant disease are crucially dependent on the recruitment and reprogramming of various immune cells. At the primary tumour site, tumour-associated macrophages and immature myeloid cells facilitate local invasion and neoangiogenesis and promote the establishment of a tumour-permissive microenvironment. Systemic cancer spread is preceded by the establishment of a permissive microenvironment in the target tissue of metastasis – the premetastatic niche. As crucial players in the establishment of the premetastatic niche as well as the orchestration of tumour immune evasion at primary tumour level, myeloid-derived suppressor cells (MDSC) release S100A8/A9, an exosomal protein that contributes to metastasis, angiogenesis, and immune suppression. S100A8/A9 is a ligand for TLR4 and RAGE and acts as a chemo-attractant to myeloid cells. The local S100A8/A9 level is a sensitive indicator of immune cell activity. Building on the development of S100A8/A9-specific optical imaging for monitoring of local inflammation, I assessed S100A8/A9 imaging for the visualisation of tumourassociated immune cell activity. I strived to establish local S100A8/A9 imaging signals to be coincident with the increased activity of tumour-promoting immune cells and therefore indicative of high malignant activity within the primary tumour and the establishment of a premetastatic niche in distant tissue. A S100A9-targeting antibody has been labelled for optical in vivo imaging and used for fluorescence imaging of tumour-associated inflammation in an orthotopic murine breast cancer model. The local S100A9-signal could be shown to reflect the tumourassociated macrophage and MDSC abundance and activity and predict local tumour growth. To enable systemic imaging of tumour-mediated immune cell activity, the optical tracer has been developed into a SPECT tracer for labelling with 111In and tested in a well-characterised murine model of local inflammation. In a syngeneic mouse model of metastatic breast cancer, S100A8/A9-SPECT sensitively reflected MDSC abundance and the establishment of an immunosuppressive environment in premetastatic lung tissue. A significant correlation between the S100A8/A9 imaging signal in the premetastatic lung and the subsequent metastatic tumour burden could be established. The results suggest S100A8/A9 as a potent imaging biomarker for monocyte activity, reflective of tumour-associated immune cell activity.
Supervisor: Schaeffter, Tobias Richard ; Ng, Tony Tsz-cheong Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.713106  DOI: Not available
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