Investigating the role of PD-L1 pathway in human ovarian cancer
File(s)
Author(s)
Chatterjee, Jay
Type
Thesis
Abstract
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 it’s 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.
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 it’s 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.
Version
Open Access
Date Issued
2014-09
Date Awarded
2014-01
Copyright Statement
Attribution NoDerivatives 4.0 International Licence (CC BY-ND)
Advisor
Ghaem-Maghami, Sadaf
George, Andrew
Publisher Department
Surgery & Cancer
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)