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Title: Integrating immune cell functions and apoptosis-based therapies for the treatment of ovarian cancer
Author: Tuthill, Mark
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2013
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High levels of regulatory T cells (Treg cells) restrict immune responses against cancer cells and are associated with adverse outcomes in patients with ovarian cancer. Treg cell development and function is regulated by the transcription factor Foxp3. Studies into the regulation of Foxp3 may identify therapeutic targets that reduce the suppressive functions of Treg cells and enhance immune responses against cancer cells. Immune cells express TNF-related apoptosis-inducing ligand (TRAIL) which can induce the death of cancer cells, whilst sparing normal tissues. The TRAIL receptor (R) agonistic drug Apo2L/TRAIL/Dulanermin, and the TRAIL-R2-specific antibody, conatumumab (AMG 655), are potential treatments for ovarian cancer. The first part of the study investigated the role of Foxo and Kruppel-like factor 2 (Klf2) transcription factors in the regulation of Foxp3. It was found that the overexpression of Foxo factors promoted TGFβ-mediated induction of Foxp3 expression in activated CD4 T cells. However, the overexpression of Klf2 antagonised the induction of Foxp3 expression by TGFβ and PI3K/Akt/mTOR inhibition. The second part of the study investigated the potential of TRAIL as a treatment for ovarian cancer. Although most primary ovarian cancer cells were resistant to TRAIL-induced apoptosis, the majority could be sensitised to TRAIL by SMAC (second mitochondrial-derived activator of caspases) mimetic treatment or proteasome inhibition. Fcγ Receptors (FcγR) are expressed on immune cells within the ovarian cancer tumour microenvironment. The in vivo agonistic, apoptosis-inducing activity of TRAIL-R2-specific antibodies, such as AMG 655, is dependent on FcγR mediated crosslinking. However, FcγR-expressing immune cells were inefficient at enabling AMG 655-induced apoptosis. It was investigated whether AMG 655 could block recombinant forms of TRAIL and thus prevent immune cells from killing cancer cells. However, potent synergy was found between AMG 655 and Apo2L/TRAIL in killing cancer cells via TRAIL-R2. These results suggest that AMG 655 and Apo2L/TRAIL/dulanermin could be combined with a SMAC mimetic drug or proteasome inhibitor to introduce a highly active TRAIL-R agonistic therapy into the cancer clinic. Therapeutic strategies that target Foxo factors or Klf2 in Treg cells; and those that combine AMG 655 and Apo2L/TRAIL/dulanermin have the potential to lead to improved outcomes in patients with ovarian cancer.
Supervisor: Walczak, Henning ; Merkenschlager, Matthias Sponsor: Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available