Researchers identify key metabolic gene as target for improved cancer immunotherapy

Researchers at the VIB-KU Leuven Cancer Biology Center have identified a potential target for cancer immunotherapy. The team, led by Professor Massimiliano Mazzone, discovered that the CDA gene is among the most upregulated metabolic genes in immunotherapy-resistant tumors.

Inhibition of this gene through pharmacological or genetic intervention led to enhanced T cell infiltration, thereby increasing the effectiveness of immunotherapy in a type of pancreatic cancer called PDAC. The results of the study were published in Natural Cancer.

Currently, immunotherapy treatments, including adoptive T cell transfer, cancer vaccines, and immune checkpoint blockade (ICB), represent a promising option for cancer patients. Despite high response rates with prolonged survival in subsets of patients with melanoma, lung and kidney cancer, ICB has difficulty demonstrating clinical benefit in several other tumors, as in most patients with colorectal cancer and pancreatic ductal adenocarcinoma (PDAC).

PDAC is one of the most aggressive and deadly cancers, with an overall five-year survival rate of 9%. In Belgium alone, pancreatic cancer is the ninth most common cancer with 2,242 diagnoses in 2021. Most patients are diagnosed at advanced stages with distant metastases, making less than 20% of patients are eligible for surgery at the time of diagnosis. Most therapies, including ICB, are not effective and many surgical patients eventually relapse.

An enzyme that tames TAMs

The team led by Professor Massimiliano Mazzone from the VIB-KU Leuven Cancer Biology Center is investigating ways to circumvent resistance to immunotherapy. In their most recent study, co-authored by Tommaso Scolaro, Marta Manco, Mathieu Pecqueux and Ricardo Amorim, the team investigated the role of an enzyme called cytidine deaminase or CDA in pancreatic ductal adenocarcinoma.

Professor Mazzone says: “CDA is an enzyme that helps recycle parts of DNA and RNA. It also disables some cancer medications, which may make these treatments less effective. Although the consensus is that CDA plays a role in resistance to chemotherapy, its role in resistance to immunotherapy has never been studied. We decided to take a closer look and determine whether CDA is indeed a barrier to treatments such as ICB.

By analyzing multiple datasets of PDAC tumors both sensitive and resistant to ICB treatment, the team proved that the presence of CDA in cancer cells results in the creation of uridine diphosphate (UDP). UDP is a molecule that can signal certain immune cells called tumor-associated macrophages (TAM). In doing so, UDP can hijack TAMs, making them immunosuppressive – an important finding, as TAMs represent approximately 50% of tumor mass and are widely associated with tumor progression.

Tommaso Scolaro, first author of the research paper, said: “Much to our excitement, our study showed that CDA does indeed contribute to resistance to immunotherapy. This led to our next hypothesis that inhibition of the gene responsible for creating CDA could in turn weaken the immunosuppressive properties of PDAC tumors that are generally resistant to treatments such as ICB.

A new genetic target

As a next step, the team investigated ways to inhibit the CDA gene in cancer cells. Through pharmacological and genetic interventions, the team was able to disrupt the interactions between cancer cells expressing CDA and TAMs. This led to enhanced T cell infiltration and greater susceptibility to immunotherapy treatments in PDAC-resistant tumors, confirming that targeting the CDA in cancer cells (or the UDP receptor in TAMs) can overcome the qualities immunosuppressive agents of a tumor. Better yet, the team also noted the same results in other types of cancer like melanoma.

Mazzone says: “The results of this study are very positive to say the least. Not only does this provide a potential new target to enable immunotherapy in resistant cancer types, but it also improves our understanding of what drives immunosuppression in tumors. of the deadliest cancers. Although our results provide hope, more research is needed before we can bring this to the patient.