Survival rate of ovarian cancer patients changed little in the last 40 years, new therapeutic approaches for ovarian cancer are desperately needed. To increase the efficacy of immunotherapy, recent studies have focused on targeting a new set of T cell inhibitory receptors in treating cancer, including LAG3. We propose to investigate how CD74, which is shaping the ligand of LAG3, is involved in ovarian tumour progression. Previously, we reported a cytokine called lymphotoxin that was overexpressed in 50% of human ovarian tumours; our data showed that its overexpression 1) promotes ovarian cancer growth and reduces survival of mice bearing ovarian tumours, 2) activates noncanonical NF-kB signalling and upregulates CD74 in ovarian cancer cells, and 3) increases infiltration of LAG3+T lymphocytes in tumour microenvironment. These findings suggested that lymphotoxin overexpression promotes tumour progression by activating noncanonical NF-kB target genes, upregulating CD74 in cancer cells and inducing T cell exhaustion in tumour microenvironment. We hypothesize that CD74, which acts as a regulator for the ligand of LAG3, promotes tumour growth by activating intracellular signalling in cancer cells and/or inducing T cell exhaustion in tumour microenvironment. We will investigate the expression and regulation of CD74 in human ovarian cancer cell lines and clinical ovarian tumour samples. We will also study the biological function(s) of CD74 in cancer progression and its regulation of the LAG3 ligand in cancer cells. Our work may lead to new targeted therapy using anti-CD74 antibody and new immune checkpoint blockade therapy using anti-LAG3 antibody for ovarian cancer patients.
The project provides the opportunity to work closely with researchers at different universities (including The Chinese University of Hong Kong), clinicians and human patient samples/data to address a pertinent clinical question that will likely lead to patient benefit. The studentship will be based at the Guy Hilton Research Centre in Hartshill. However, there will be the occasional need to attend training at Keele University campus.
Please ensure you quote FMHS_JKJULY2022 in your application, to ensure it is considered for the funded opportunity.
For application, please visit: https://www.keele.ac.uk/study/postgraduateresearch/studentships/investigationofmhcclassiiaccessorymoleculecd74inhumanovariancancer/