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Title: Investigating the role of PD-L1 pathway in human ovarian cancer
Author: Chatterjee, Jay
ISNI:       0000 0004 5349 4315
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2014
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Ovarian cancer has the highest mortality among malignancies of the female reproductive tract. Negative regulatory mechanisms within the tumour microenvironment inhibit anti-tumour T-cell function, leading to evasion from immune responses. The binding of PD-L1, expressed on antigen presenting cells to PD-1 on activated T cells, is thought to result in an important T-cell inhibitory mechanism and promote immune evasion. We have shown that increased PD-L1 expression on monocytes correlates with malignancy, advanced stage and surgical debulking status in ovarian cancer. We have also studied PD-L1 expression on T-cells in women with ovarian tumours and its relation with diagnosis. We have devised a sandwich ELISA to accurately detect the presence of soluble PD-L1 in the plasma and ascites of patients with ovarian cancer and have shown increased presence of soluble PD-L1 in women with ovarian cancer when compared with benign ovarian tumours and healthy female donors. We have found high expression of PD-L1 at mRNA and protein level in all serous ovarian cancer cell lines. We have investigated the role of PD-1/PD-L1 engagement in in vitro T-cell responses, using ovarian cancer cell lines. We have shown that PD-L1/PD-1 engagement in tumour and T-cell interaction is associated with reduced T cell proliferation. In an in vitro model of ovarian cancer cell line and stimulated T-cell co-culture we have shown that blocking PD-L1, PD-1 and key cytokines reverse T cell 'suppression' and increase proliferation. We have also demonstrated that IL-10 and TGF-β play an important role in regulation of PD-L1 expression on tumour associated monocytes. We have also shown that ascitic monocytes suppress the proliferation of both ascitic T-cells and healthy stimulated T-cells. This suppression by tumour associated monocytes can be completely reversed by combined blocking of PD-L1, PD-1 and IL-10 to the baseline proliferation of T-cells cultured. This research has shown that PD-L1 can be a potential biomarker and therapeutic target in ovarian cancer.
Supervisor: Ghaem-Maghami, Sadaf; George, Andrew Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available