Systemic and colonic changes in dendritic cell characteristics in development and progression of colorectal cancer
File(s)
Author(s)
Lee, Gui Han
Type
Thesis
Abstract
Dendritic cells (DCs) are specialized antigen presenting cells, which recognize, acquire and present tumour antigens to adaptive immune cells for effective anti-tumour immune response. Colorectal cancer (CRC) is a leading cause of cancer mortality in UK. The potential role of DC-based immunotherapy in adjunct to conventional CRC treatment has not yet been fully explored. Research to-date suggests that the theory of tumour immunoediting is applicable to CRC, but there is limited evidence on the role of DCs in this process.
The overall aim of the work in this thesis was to identify differences in systemic and colonic DC characteristics between healthy controls, “pre-cancer” groups (FAP and UC with higher risk of CRC) and CRC patients. Furthermore, “host” and “disease” factors influencing systemic and colonic DCs were investigated.
Results demonstrated that systemic DCs in CRC were more activated and lymph node migratory. The proportion of “homeless” DCs and circulating Th-1 cytokines were significantly higher in CRC.
There was evidence of colonic DC compartmentalization depending on the location of CRC. Tumoral DCs were more activated and lymph node migratory but remained phenotypically immature. Immunohistochemical analysis demonstrated that tumour cells mediate the up- regulation of CCR7 in tumour-infiltrating cells, whereas tumour-associated adipocytes mediated the up-regulation of scavenger receptor (CD36) in tumour-infiltrating cells.
In vitro colonic DC conditioning with leptin led to up-regulation of scavenger receptors, but not in systemic DCs, highlighting the potential importance of mesenteric adipocyte-derived factors in tumour-mediated DC modulation.
This study highlighted that changes in systemic and colonic DC characteristics occur after development of CRC. Both tumour-derived and patient factors play an essential role in modulating DC characteristics. Tumour-associated adipocytes and adipokines have a role in colonic DC modulation in CRC. Further studies are required to explore the potential pathways of DC immunomodulation in CRC which has been identified in this study.
The overall aim of the work in this thesis was to identify differences in systemic and colonic DC characteristics between healthy controls, “pre-cancer” groups (FAP and UC with higher risk of CRC) and CRC patients. Furthermore, “host” and “disease” factors influencing systemic and colonic DCs were investigated.
Results demonstrated that systemic DCs in CRC were more activated and lymph node migratory. The proportion of “homeless” DCs and circulating Th-1 cytokines were significantly higher in CRC.
There was evidence of colonic DC compartmentalization depending on the location of CRC. Tumoral DCs were more activated and lymph node migratory but remained phenotypically immature. Immunohistochemical analysis demonstrated that tumour cells mediate the up- regulation of CCR7 in tumour-infiltrating cells, whereas tumour-associated adipocytes mediated the up-regulation of scavenger receptor (CD36) in tumour-infiltrating cells.
In vitro colonic DC conditioning with leptin led to up-regulation of scavenger receptors, but not in systemic DCs, highlighting the potential importance of mesenteric adipocyte-derived factors in tumour-mediated DC modulation.
This study highlighted that changes in systemic and colonic DC characteristics occur after development of CRC. Both tumour-derived and patient factors play an essential role in modulating DC characteristics. Tumour-associated adipocytes and adipokines have a role in colonic DC modulation in CRC. Further studies are required to explore the potential pathways of DC immunomodulation in CRC which has been identified in this study.
Version
Open Access
Date Issued
2016-10
Date Awarded
2017-06
Copyright Statement
Attribution NoDerivatives 4.0 International Licence (CC BY-ND)
Advisor
Clark, Susan K.
Knight, Stella
Publisher Department
Department of Medicine
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)