Role of Properdin in Tumour Growth and Cell Recruitment

    Student thesis: Doctoral Thesis


    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.
    Date of Award23 Jun 2017
    Original languageEnglish
    Awarding Institution
    • University of Leicester
    SupervisorCordula Stover (Supervisor), Lee Machado (Supervisor) & Michael Browning (Supervisor)

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