Potential targets for cancer immunotherapy: research

Researchers have discovered a potential target for cancer immunotherapy. Research directed by Professor Massimiliano Mazzone found that the CDA gene is one of the most metabolic genes upregulated in immunotherapy-resistant cancers. Inhibiting this gene through pharmacological or genetic intervention improved T-cell infiltration, increasing the efficacy of immunotherapy in PDAC, a type of pancreatic cancer.

The study was conducted by the VIB-KU Leuven Centre for Cancer Biology and the findings were published in Nature Cancer.

Also Read: Pancreatic cancer: Causes, symptoms, treatment and prevention tips

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 long-term survival in subgroups of patients with melanoma, lung and kidney cancer, ICB struggles to show clinical benefit in most patients with several other tumors such as colorectal cancer and pancreatic ductal adenocarcinoma (PDAC).

PDAC is one of the most aggressive and deadly cancers, with an overall 5-year survival rate of 9%. In Belgium alone, pancreatic cancer is the 9th most common cancer with 2242 diagnoses in 2021. Most patients are diagnosed at advanced stages with distant organ metastasis, resulting in less than 20% of patients being eligible for surgery at the time of diagnosis. Most treatments, including ICB, are not effective and many patients who undergo surgery eventually relapse.

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

Professor Massimiliano Mazzone says, “CDA is an enzyme that helps recycle parts of DNA and RNA. It also inactivates some cancer drugs, which can make these treatments less effective. While the consensus is that CDA plays a role in resistance to chemotherapy, its role in immunotherapy resistance has never been studied. We decided to take a closer look at this and determine whether CDA is truly an obstacle to treatments such as ICB.”

By analysing multiple datasets of PDAC tumours that were both responsive and resistant to ICB treatment, the team proved that the presence of CDA in cancer cells results in the build-up of uridine-diphosphate (UDP). UDP is a molecule that can signal to certain immune cells known as tumour-associated macrophages (TAMs). In doing so, UDP can hijack TAMs, making them immunosuppressive. An important finding, as TAMs make up around 50% of tumour mass and are widely associated with tumour progression.

“To our excitement, our study showed that CDA actually contributes to immunotherapy resistance. This led to our next hypothesis that inhibiting the gene responsible for making CDA could weaken the immunosuppressive properties of PDAC tumors, which are typically resistant to treatments such as ICBs,” said Tommaso Scolaro, first author of the research paper.

As a next step, the team looked at ways to inhibit the CDA gene in cancer cells. Through pharmacological and genetic intervention, the team was able to disrupt the interactions between CDA expressing cancer cells and TAMs. This led to improved infiltration of T-cells and greater sensitivity to immunotherapy treatments in resistant PDAC tumors, confirming that targeting CDA (or the UDP receptor in TAMs) in cancer cells could overcome the immune suppressive properties of tumors. Even better, the team also observed similar results in other cancer types, such as melanoma.

Massimiliano Mazzone says, “The results of this study are very positive. It not only proposes a new potential target to enable immunotherapy in resistant cancer types, but it also improves our understanding of the factors that induce immunosuppression in tumors. PDAC is one of the most deadly cancers. While our results are hopeful, more research is needed before we can bring this to patients.”