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Title: Tissue-specific immunoregulatory mechanisms in solid tumours
Author: Ganesan, A. P.
ISNI:       0000 0001 2450 7349
Awarding Body: University of Southampton
Current Institution: University of Southampton
Date of Award: 2012
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Tumour infiltrating lymphocytes are detected in many patients with solid tumours and it is well established in colorectal cancer (CRC) that they have a direct correlation with survival. However it is not clear why this beneficial immune response is impaired in some patients. Since T regulatory cell (Tregs) infiltrates are common to multiple solid tumour types, where their presence has been associated with poor prognosis, we hypothesized that Tregs infiltrating colorectal tumours functionally contribute to pro-tumour immunity and thereby promote colorectal tumour progression. Using multicolour flow cytometry, we characterised the immune infiltrate in blood, colorectal tumour tissue and liver metastases from patients with colorectal cancer. We found that whilst the CD4+CD2Shi fraction was significantly increased in the peripheral blood of CRC patients, the CD4+Foxp3+ fraction that represents the true T regulatory cells, were not increased in patients as compared to disease- free controls. In marked contrast, the CD4+Foxp3+ T regulatory cells were significantly increased in the colorectal tumour and in the metastatic tumour tissue (hepatic metastases) relative to the adjacent normal tissue obtained from the patients. Using an in vitro microculture system to assess T regulatory cell function, we revealed the differential suppressive ability of the T regulatory cells from different compartments such as the blood and tumour tissue and the differential susceptibility of the T effector cells to be suppressed by Tregs from these compartments. Both the blood-derived Tregs and the tumour-infiltrating Tregs suppressed proliferation of autologous tumour effectors in 7 out of 9 CRC patients and suppressed interferon-y production in 7 out of S patients. In order to determine the functional significance of Tregs in vivo, we utilised a transgenic mouse model of solid tumour development, namely, CC 1 O-TAg. We found that CD4+Foxp3+ Tregs were enriched within mouse tumours and that endogenous anti-tumour CDS+ T cell responses were critical in controlling tumour growth. Using anti-CD25 depleting antibodies that effectively deplete CD25- expressing CD4+FoxP3+ Tregs in CCIO-TAg mice at an early stage of tumour development, we found a significant reduction in tumour burden relative to control mice. This was accompanied by increased infiltration of tumours with cytotoxic CDS' T cells that were characterized by enhanced gene expression of cytotoxic molecules, granzy me A, granZ) me B and perforin. In addition, both CD4' effector T cells and CDS' cytotoxic T cells displayed up-regulation of interferon-y expression following Treg depletion, all of which culminated in increased tumour cell apoptosis. We further tested the therapeutic potential of Treg depletion in combination with chemotherapy (carboplatin) in the more clinically relevant established tumours and demonstrated significant extension of survival in tumour- bearing mice. Taken together, our data have important application in designing novel immunotherapeutic strategies that target Tregs for the treatment of cancer.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available