Targeting a protein to make ovarian cancers more susceptible to immune checkpoint blockade therapy 

Professor Khanna’s team is working to improve outcomes for people with high-grade serous ovarian cancer (HGSOC), the most common subtype of ovarian cancer. While immunotherapy has transformed treatment for several cancer types, it has been less successful in HGSOC, highlighting a significant unmet need for new approaches.

Immune cells, including CD8+ T cells which are some of the body’s key cancer-fighting immune cells, are present in many ovarian tumours, and often fail to mount a strong or long-lasting response. This suggests that these ovarian tumours have developed mechanisms to avoid immune detection and destruction or actively suppress the immune system, limiting the effectiveness of immunotherapy treatments such as anti-PD-1 therapies.

Professor Khanna and her team are investigating a protein called PP2A, which plays a role in many cellular processes, including how the immune system recognises cancer cells. Recent evidence has suggested that PP2A may contribute to immune evasion in certain contexts, including ovarian cancer.

Research in other cancer types has shown that blocking PP2A can enhance responses to immunotherapy. In addition, ovarian cancers with changes in PP2A-related genes, which impact the way the protein is produced or functions, have shown particularly strong responses to immune-based treatments.

The team’s own laboratory studies further support this approach. They have found that ovarian tumours with lower levels of PP2A-related proteins tend to have more active immune cells, and that blocking PP2A in experimental models can increase immune activation and make tumour cells more visible to the immune system. Together, these findings suggest that targeting PP2A could help overcome some of the barriers limiting immunotherapy effectiveness in HGSOC.

In this project, the team will investigate whether blocking PP2A can make ovarian cancer more responsive to immune checkpoint inhibitors (ICIs) like anti-PD-1 therapy, a type of immunotherapy that works by releasing the ‘brakes’ on immune cells, helping them recognise and attack cancer cells.

First, they will use organoids, miniature tumour models grown from patient samples, to examine how PP2A-blocking drugs influence the tumour environment and improve cancer-fighting T cell activity. These models allow the team to closely replicate key features of human tumours in the laboratory. They will test two different PP2A-blocking drugs to confirm that the effects they observe are specifically due to PP2A. The team will look at whether blocking PP2A switches on immune-signaling pathways, making cancer cells show more 'flags' that help immune cells recognise them, and changing which pieces of tumour proteins appear on the cell surface, potentially giving the immune system new targets to attack.

Next, the team will test the combination of PP2A inhibitors and ICIs in preclinical models of HGSOC to determine whether this approach can slow tumour growth. They will carry out detailed profiling of the immune cells within and around the tumour to understand how the treatment reshapes the immune environment, including whether it increases the number of active cancer-fighting T cells or reduces immune-suppressing cells that can shield the tumour.