2017ALRAYAHI_IZ_PhD.pdf (4.84 MB)
The role of Properdin in Tumour Development and Cell Recruitment
thesisposted on 2017-06-26, 12:11 authored by Izzat Abdulsatar Mezher Al-Rayahi
Properdin, as the only positive regulator, amplifies complement activation and has been implicated in the tumour response in human lymphoma and carcinoma. This project investigated the role of properdin in a syngeneic orthotopic tumour model in mice engineered to be properdin deficient and their wildtype controls. The in vitro part of the project used macrophages differentiated from bone marrows of these mice and stimulated with conditioned medium of a syngeneic mouse melanoma cell line, B16F10. In comparison with macrophages from wildtype mice, macrophages from congenic properdin deficient mice showed skewing towards M2 profile, encompassing mRNA expression for genes involved in arginine metabolism, production of type 2 cytokines, and relatively lower surface expression of molecules needed for antigen presentation suggesting that properdin insufficiency promotes a tumour environment that helps the tumour evade the immune response. The in vivo part of this project established the immune profile of tumour bearing mice. MDSCs, C5a, CCL2, TGF-β and mRNA FOXP3 were significantly less abundant in tumours of properdin deficient compared to wildtype mice. Protein levels for CCL2, a chemokine associated with tumour progression, was higher in wildtype tumour bearing mice. In spleen, MDSCs, regulatory T cells, M2 macrophages (CD206+F4/80+) and TGF-β were decreased significantly in properdin deficient compared with wildtype mice (control) after subcutaneous injection with B16F10 cells, indicating that properdin may contribute to the accumulation of MDSCs in spleen, as well as to the migration of these cells into tumours. LDLR-/- mice group were analysed in parallel because of their inherently greater M2 skewing. An advanced bioimaging technique was applied to some of the experimental animals. Analysis of the level of serum properdin in response to treatment in a group of patients with pancreatic cancer showed high levels in this group. In conclusion, this project identified complement properdin as significant in the macrophage response to conditioned melanoma cell medium, in the composition of the tumour microenvironment and systemic response to tumour in vivo and as an acute responder to chemotherapy in patients with pancreatic cancer.
Supervisor(s)Stover, Cordula; Browning, Michael
Date of award2017-06-23
Author affiliationDepartment of Infection, Immunity and Inflammation
Awarding institutionUniversity of Leicester