Researchers have discovered a possible target for cancer immunotherapy. The research, directed by Professor Massimiliano Mazzone, discovered that the CDA gene is one of the most elevated metabolic genes in immunotherapy-resistant cancer. Inhibiting this gene through pharmacological or genetic intervention resulted in improved T-cell infiltration, enhancing the efficacy of immunotherapy in PDAC, a type of pancreatic cancer.
Study done by VIB-KU
Leuven Center for Cancer Biology and findings were published in Nature Cancer.
At present,
immunotherapy treatments, including adoptive T-cell transfer, cancer vaccines
and immune checkpoint blockade (ICB), represent a promising option for cancer
patients. Despite the high response rates with prolonged survival in subsets of
melanoma, lung, and renal cancer patients, ICB struggles to show clinical
benefit in several other tumors such as in most of colorectal cancer and
pancreatic ductal adenocarcinoma (PDAC) patients.
PDAC is one of the most
aggressive and lethal 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 being eligible for
surgery at the time of diagnosis. Most therapies, including ICB, are not
effective and many patients who undergo surgery ultimately 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 Pecqueux 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 deactivates 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 was never studied. We decided to take a
closer look and to determine if CDA is indeed a roadblock for treatments such
as ICB."
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 creation of uridine-diphosphate (UDP). UDP is a molecule that can signal
certain immune cells known as tumor-associated macrophages (TAMs). In doing so,
UDP can hijack TAMs, turning them immunosuppressive. An important finding,
because TAMs make up approximately 50% of tumor mass and are widely associated
with tumor progression.
Tommaso Scolaro, first
author of the research paper, "To our excitement, our study showed that
CDA indeed contributes to immunotherapy resistance. This led to our next
hypothesis that inhibiting the gene responsible for creating CDA could in turn
weaken the immunosuppressive properties of PDAC tumors that are typically
resistant to treatments such as ICB."
As a next step, the team
looked at ways to inhibit the CDA gene in cancer cells. Through pharmacologic
and genetic interventions, the team was able to disrupt the interactions
between CDA expressing cancer cells and TAMs. This led to better infiltration
of T-cells and a higher susceptibility for immunotherapy treatments in
resistant PDAC tumors, confirming that targeting CDA in cancer cells (or the
UDP receptor in TAMs) can overcome the immunosuppressive qualities of a tumor.
Better yet, the team also noted the same results in other cancer types such as
melanoma.
Massimiliano Mazzone,
"The results of this study are very positive to say the least. 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 tumors. PDAC is one of the deadliest cancers out there.
While our results give hope, more research is needed before we can bring this
to the patient."
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