Leuven [Belgium], Researchers have discovered a potential target for cancer immunotherapy. Research directed by Professor Massimiliano Mazzone revealed that the CDA gene is one of the most upregulated metabolic genes in immunotherapy-resistant cancers. Disrupting this gene through pharmacological or genetic intervention improved T-cell infiltration, thereby increasing the efficacy of immunotherapy in PDAC, a type of pancreatic cancer.
The study, conducted by the VIB-KU Leuven Center for Cancer Biology, and the findings were published in Nature 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 long-term survival in subgroups of melanoma, lung and kidney cancer patients, ICBs show clinical benefit in the majority of patients with several other tumors such as colorectal cancer and pancreatic ductal adenocarcinoma (PDAC). Struggles for.
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 metastases, resulting in less than 20% of patients eligible for surgery at the time of diagnosis. Most treatments, including ICBs, are not effective and many patients who undergo surgery eventually relapse.A team led by Professor Massimiliano Mazzone at the VIB-KU Leuven Center for Cancer Biology investigates ways to bypass immunotherapy resistance. In their most recent study, co-authored by Tommaso Scolaro, Marta Manco, Mathieu Pequeux and Ricardo Amorim, the team studied the role of an enzyme called cytidine deaminase, or CDA, in pancreatic ductal adenocarcinoma.
Professor Massimiliano Mazzone, "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 general consensus is that While CDA plays a role in resistance to chemotherapy, its role in immunotherapy resistance has never been studied.We decided to take a closer look and determine whether CDA is indeed a barrier to treatments like ICBs."
By analyzing multiple datasets of PDAC tumors that were both responsive and resistant to ICB treatment, the team proved that the presence of CDA in cancer cells results in the formation of uridine-diphosphate (UDP). UDP is a molecule that can signal to certain immune cells known as tumor-associated macrophages (TAMs). In doing so, UDP can hijack TAMs and render them immunosuppressive. An important finding, as TAMs make up approximately 50% of tumor mass and are widely associated with tumor progression.Tommaso Scolaro, first author of the paper, said, "To our excitement, our study showed that CDA does indeed contribute to immunotherapy resistance. This led to our next hypothesis that inhibiting the gene responsible for making CDA may help in the development of PDAC tumors. "Can weaken immunosuppressive properties that are generally resistant to treatments such as ICBs."
As a next step, the team looked at ways to inhibit the CDA gene in cancer cells. Through pharmacological and genetic interventions, the team was able to disrupt the interaction between CDA-expressing cancer cells and TAMs.This led to better infiltration of T-cells and higher sensitivity to immunotherapy treatment in resistant PDAC tumors, confirming that targeting CDA in cancer cells (or the UDP receptor in TAMs) can overcome the immunosuppressive properties of tumors. . Even better, the team also saw similar results in other cancer types, such as melanoma.
Massimiliano Mazzone, "The results of this study are very positive, to say the least. It not only proposes a new potential target to enable immunotherapy in resistant cancer types, but it also provides insight into what drives immunosuppression in tumors." PDAC is one of the deadliest cancers."Although our results offer hope, more research is needed before we can bring it to patients."
The study, conducted by the VIB-KU Leuven Center for Cancer Biology, and the findings were published in Nature 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 long-term survival in subgroups of melanoma, lung and kidney cancer patients, ICBs show clinical benefit in the majority of patients with several other tumors such as colorectal cancer and pancreatic ductal adenocarcinoma (PDAC). Struggles for.
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 metastases, resulting in less than 20% of patients eligible for surgery at the time of diagnosis. Most treatments, including ICBs, are not effective and many patients who undergo surgery eventually relapse.A team led by Professor Massimiliano Mazzone at the VIB-KU Leuven Center for Cancer Biology investigates ways to bypass immunotherapy resistance. In their most recent study, co-authored by Tommaso Scolaro, Marta Manco, Mathieu Pequeux and Ricardo Amorim, the team studied the role of an enzyme called cytidine deaminase, or CDA, in pancreatic ductal adenocarcinoma.
Professor Massimiliano Mazzone, "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 general consensus is that While CDA plays a role in resistance to chemotherapy, its role in immunotherapy resistance has never been studied.We decided to take a closer look and determine whether CDA is indeed a barrier to treatments like ICBs."
By analyzing multiple datasets of PDAC tumors that were both responsive and resistant to ICB treatment, the team proved that the presence of CDA in cancer cells results in the formation of uridine-diphosphate (UDP). UDP is a molecule that can signal to certain immune cells known as tumor-associated macrophages (TAMs). In doing so, UDP can hijack TAMs and render them immunosuppressive. An important finding, as TAMs make up approximately 50% of tumor mass and are widely associated with tumor progression.Tommaso Scolaro, first author of the paper, said, "To our excitement, our study showed that CDA does indeed contribute to immunotherapy resistance. This led to our next hypothesis that inhibiting the gene responsible for making CDA may help in the development of PDAC tumors. "Can weaken immunosuppressive properties that are generally resistant to treatments such as ICBs."
As a next step, the team looked at ways to inhibit the CDA gene in cancer cells. Through pharmacological and genetic interventions, the team was able to disrupt the interaction between CDA-expressing cancer cells and TAMs.This led to better infiltration of T-cells and higher sensitivity to immunotherapy treatment in resistant PDAC tumors, confirming that targeting CDA in cancer cells (or the UDP receptor in TAMs) can overcome the immunosuppressive properties of tumors. . Even better, the team also saw similar results in other cancer types, such as melanoma.
Massimiliano Mazzone, "The results of this study are very positive, to say the least. It not only proposes a new potential target to enable immunotherapy in resistant cancer types, but it also provides insight into what drives immunosuppression in tumors." PDAC is one of the deadliest cancers."Although our results offer hope, more research is needed before we can bring it to patients."
