cGAS-STING as a regulator of response to immunotherapy in HGSOC

"High grade serous ovarian cancer (HGSOC) remains the most lethal gynecological malignancy despite the introduction of targeted therapies in the clinic such as PARP inhibitors and anti-angiogenics. Immune checkpoint blockade (ICB) targeting the PD-1-PD-L1 signaling axis has provided substantial clinical benefit to patients across several cancer types. However, HGSOC patients fail to respond to ICB, both as a monotherapy and in combination with DNA damaging agents in clinical trials. cGAS-STING signaling has been shown to be important in anti-tumour immunity, such that activation promotes T cell recruitment and activation, as well as increasing tumour PD-L1 expression. This signaling cascade is activated by cytosolic DNA, often as a result of DNA damaging agents or due to chromosomal instability. Approximately 50% of HGSOC patients have defective homologous recombination repair, inducing chromosomal instability and DNA damage. We hypothesise that defective cGAS-STING signaling may contribute to lack of response to ICB in HGSOC cells.
Our preliminary data suggests that STING expression is required for efficient PD-L1 expression following PARP inhibitor or cGAMP treatment. We are currently screening a panel of human HGSOC cell lines for defects in the cGAS-STING signaling pathway to understand what defects in this pathway are common in HGSOC. Given PD-L1 is induced by DNA damage, we are currently investigating the role of the second ligand for PD-1, PD-L2, in the response to DNA damaging agents. Our preliminary experiments suggest that significantly less PD-L2 expression is induced at the RNA, protein, and cell surface level, in response to different DNA damaging agents, in comparison to PD-L1 expression.
Taken together, in this project we aim to determine the role of cGAS-STING signaling in the response to ICB in HGSOC and whether PD-L2 is regulated by DNA damage in human tumour cells, similar to PD-L1."