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Title: Regulated antagonism of immune suppressive molecules in tumours
Author: Alamoudi, Aliaa
ISNI:       0000 0004 5349 1018
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2014
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Despite expressing antigens that can induce immune surveillance and immune eradication, tumours demonstrate the capacity to evade anti-tumour immunity. Recently, this has been attributed to the ability of tumours to induce a local immunosuppressed micro-environment, which is a major obstacle to successful natural and vaccine induced anti-tumour immunity. Soluble factors such as transforming growth factor beta (TGFβ), and interleukin 10 (IL-10), released by cancer and stromal cells, are thought to play a significant role in this local immunosuppression. In order to assess the influence of antagonising these soluble factors locally on tumour biology and tumour immunity, a murine CT26 colorectal carcinoma model that can express cytokine antagonists under Doxycycline (Dox) control was engineered. Two stable CT26 cell lines expressing Dox-inducible soluble extracellular domain of TGFβ receptor II (STGFβRII) or soluble extracellular domain of IL-10 receptor (SIL-10R), were established. Expression of STGFβRII in vitro and in vivo was only evident after Dox treatment. When Dox was administered directly following subcutaneous (s.c.) inoculation of STGFβRII-expressing CT26 cells into Balb/c mice, tumour growth was significantly suppressed. Interestingly, inducing STGFβRII in well-established tumours showed less suppression of tumour growth. To assess the effect of expressing STGFβRII on tumour immunity the RNA expression of 22 common cytokines was measured in the tumours of mice receiving Dox and control mice. The levels of some of these cytokines were modulated by STGFβRII expression (e.g TGFβ,Tnfsf9, IL-2). We also tested for any additive effect between expressing STGFβRII, and the administration of anti-CTLA-4 antibody on tumour growth, and tumour immunity. The model described here could help address various limitations seen previously in studies of TGFβ blockade. It provides means of effective local antagonism, and it addresses immunological endpoints which have been limited in previous studies. Because of its tight regulation, the model also allows identification of the best timing of TGFβ blockade alone or in combination with other immunotherapeutics.
Supervisor: Seymour, Len; Carlisle, Robert Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Oncology ; tumours ; gene therapy ; immunotherapy