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Title: Tumour-mediated inhibition of natural killer cells
Author: El-Jawhari, Jehan Jomaa El-Said.
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2010
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The critical role of immune cells, in particular NK cells and cytotoxic T lymphocytes in recognition and elimination of tumour cells has been clearly demonstrated. However, immune evasion is a central hallmark of cancer; it negatively influences the prognosis and efficiency of therapies. Thus, understanding of this process will help to improve cancer therapy. Genetic alterations such as activation of oncogenes and loss of tumour suppressor genes are highly implicated in carcinogenesis. This study shows that the presence of KRAS oncogene reduced the surface expression of MHC class I on colorectal tumour cells and lead to suppression of CTL response. In contrast, the expression of KRAS oncogene did not affect the susceptibility of colorectal tumour cells to NK. cell killing nor inhibit NK cell functions. This suggests that targeting of the KRAS oncogene in colorectal tumours to improve CTL responses would be of a therapeutic benefit. In contrast, loss of a tumour suppressor gene, VHL in renal tumour cells was associated with reduced inhibitory effects on NK cells. Further investigations into how tumour cells inhibit NK cells were performed via an assessment of the role for an immunosuppressive cytokine, TGF-β Interestingly, the data show that TGF-β participates in colorectal tumour-mediated modification of the surface expression of NK cell receptors as well as suppression of NK cell functions. Supporting in vitro results, malignant ovarian tumour cells (ascitic-derived) had an inhibitory effect on the phenotype and activities of NK cells. Importantly, TGF-β was involved in these suppressive effects. My data strongly support targeting of TGF-β in therapy of colorectal and ovarian cancers to enhance anti-tumour responses ofNK cells.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available