Study Title: Non-conventional approaches to “actionable vaccine targets” for granulosa cell tumour immunotherapy

Granulosa cell tumours (GCT) arise from granulosa cells (GC) of the ovarian follicle, and represent a specific subset of malignant ovarian tumours. There are two subtypes of GCT: the more common adult (aGCT) and the rarer juvenile (jGCT) form, jGCT represent approximately 5% of all GCT. GCT are unusual in that they have an unexplained propensity for late recurrence. ~80% of patients with aggressive or recurrent tumours die from their disease. At present there are no reliable methods for predicting relapse and, aside from surgery, no therapeutic modalities have proven effective. It is critically important to understand the molecular mechanisms contributing to the pathogenesis of GCT.

There have been some investigations into the use of immunotherapy for the treatment of GCT, although research in this area is still very limited. Immunotherapies, such as immune checkpoint inhibitors, have shown promise in treating other ovarian cancers, however the response rates are low due to pre-existing anti-tumour immunity.

Cancer immunopeptidomics is an emerging field that focuses on the identification and characterisation of peptides presented on the surface of cancer cells in the context of major histocompatibility complex (MHC) molecules. These peptides, also known as tumour-associated antigens (TAAs), can be recognised by the immune system and trigger an anti-tumour immune response. The following proposal will be applicable to both the adult and juvenile GCT types.

This project aims to understand the landscape of TAAs in GCT as a crucial step to develop novel cancer immunotherapies. We will apply state-of-the-art mass spectrometry-based techniques to comprehensively profile the immunopeptidome of GCT cells, with the ultimate goal of identifying new TAAs and improving immunotherapy strategies.

Further, to broaden these findings, we will then apply this knowledge to a new area of research, which involves the creation of cancer vaccines (either DNA or mRNA) that help the body’s immune system to recognise and fight cancer cells that it may not have recognised before. These vaccines can help to generate new immunity against the tumour. Hence, in this aim, we will develop the cancer vaccines towards the newly discovered TAAs from our first aim, and assess their efficacy in GCT-derived cell lines and in an animal model for GCT. The outcome of these studies will provide a proof-of-concept for clinical trials involving the most efficacious cancer vaccine either alone or in combination with immune checkpoint inhibitors.