Discovery and therapeutic exploitation of immunological vulnerabilities in ovarian cancer

The overall goal is to uncover the immune regulatory cell types and their functional networks to develop new immunotherapeutic strategies for patients with high-grade serous ovarian cancer (HGSOC). A key event in tumor progression is the establishment of an immunosuppressive milieu that prevents the immune system from attacking the tumor cells. The mechanisms of immune evasion in HGSOC are poorly understood. Interestingly, preliminary evidence suggests that DNA damaging agents, such as platinum and Poly-ADP Ribose Polymerase (PARP) inhibitors, activate specific stimulatory, and also suppressive immune regulatory pathways in distinct molecular subtypes of HGSOCs. There now is a critical need for a deeper understanding of the regulatory cell types and pathways and the dynamics of DNA damaging agents in HGSOC tumor microenvironment to aid in patient stratification and development of new immunotherapeutic strategies in HGSOC.

We propose to discover the immune-cell subtypes, functional states, and pathways that contribute to immune regulation in HGSOC. We are using state-of-the-art sequencing and bioinformatic analyses, and a cutting-edge single-cell imaging platform (tCycIF) on an internationally unique clinical dataset of over 1000 patients, collected both before and after DNA damaging therapies. tCycIF is a revolutionary highly-multiplexed technology able to analyze up to 60 antigens on the same clinical tumor sample at single-cell resolution, allowing for the analysis of spatial cell-cell interactions. The clinically relevant immunological features will be functionally validated in short-term organoid cultures. The results will reveal the mechanisms of immune evasion and the effects of DNA-damaging agents on the tumor microenvironment in HGSOC molecular subtypes. The proposed project has an unprecedented potential to discover critical immunological vulnerabilities and biomarkers to improve the treatment and outcomes of patients with HGSOC.