In a groundbreaking discovery, researchers have identified a promising new target for cancer immunotherapy. The research, led by Professor Massimiliano Mazzone at the VIB-KU Leuven Center for Cancer Biology, has pinpointed the cytidine deaminase (CDA) gene as a key player in immunotherapy-resistant cancers. This finding, published in the prestigious journal Nature Cancer, offers fresh hope for patients struggling with some of the most challenging cancer types, including pancreatic ductal adenocarcinoma (PDAC).
PDAC, known for its aggressive nature and poor prognosis, has long been a formidable adversary in the field of oncology. With an overall five-year survival rate of just 9%, and most diagnoses occurring at advanced stages, effective treatments have remained elusive. Immunotherapy, including adoptive T-cell transfer, cancer vaccines, and immune checkpoint blockade (ICB), has shown promise in certain cancers like melanoma, lung, and renal cancers. However, it has had limited success in PDAC and other tough-to-treat tumours.
The study led by Professor Mazzone and his team, including co-authors Tommaso Scolaro, Marta Manco, Mathieu Pecqueux, and Ricardo Amorim, sheds light on the role of the CDA enzyme in PDAC. “CDA is an enzyme that helps recycle parts of DNA and RNA and can deactivate some cancer drugs, making treatments less effective,” explains Mazzone. While CDA’s role in chemotherapy resistance is well-documented, its impact on immunotherapy resistance was previously unexplored.
The researchers analyzed multiple datasets of PDAC tumours, both responsive and resistant to ICB treatment. They discovered that the presence of CDA in cancer cells leads to the production of uridine-diphosphate (UDP), a molecule that signals tumor-associated macrophages (TAMs). TAMs, which constitute approximately 50% of the tumour mass, become immunosuppressive under the influence of UDP, promoting tumour progression.
“Our study showed that CDA contributes to immunotherapy resistance,” says Tommaso Scolaro, the first author of the research paper. This revelation led the team to hypothesize that inhibiting the CDA gene could diminish the immunosuppressive properties of PDAC tumours, making them more susceptible to treatments like ICB.
Through both pharmacologic and genetic interventions, the researchers were able to inhibit the CDA gene in cancer cells, disrupting the interactions between CDA-expressing cancer cells and TAMs. This intervention enhanced T-cell infiltration and increased the efficacy of immunotherapy in previously resistant PDAC tumours. The study also observed similar results in other cancer types, such as melanoma, suggesting a broader application for this approach.
“The results of this study are very positive,” remarks Mazzone. “Not only does this propose a new potential target to enable immunotherapy in resistant cancer types, but it also improves our understanding of what drives immunosuppression in tumours. PDAC is one of the deadliest cancers, and while our results give hope, more research is needed before we can bring this to the patient.”
This discovery marks a significant advance in the fight against cancer, offering a new strategy to overcome the formidable challenge of immunotherapy resistance. As researchers continue to explore the potential of targeting the CDA gene, there is renewed optimism for developing more effective treatments for some of the most lethal forms of cancer.
