AbstractProperdin, 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.
|Date of Award||23 Jun 2017|
|Supervisor||Cordula Stover (Supervisor), Lee Machado (Supervisor) & Michael Browning (Supervisor)|