For patients and doctors alike, pancreatic cancer remains one of medicine’s most formidable foes. The disease often lurks silently for years, evading detection until symptoms appear—by which point, treatment is far more difficult. Even after surgery removes the primary tumor, cancer cells can lie dormant, only to reemerge with devastating consequences. Now, a breakthrough from University of Rochester Medicine researchers offers new hope: a deeper understanding of how pancreatic cancer hides from the immune system, and how that knowledge could lead to more effective therapies.
In a study published in Developmental Cell, surgeon-scientist Darren Carpizo and his team at the Wilmot Cancer Institute identified a previously unknown role for the gene Dec2 in helping pancreatic cancer cells evade the body’s immune defenses. Their discovery not only explains why some immunotherapies fail in pancreatic cancer but also suggests a new target for treatment—and even a potential explanation for why timing might matter when administering those therapies.
Pancreatic cancer’s five-year survival rate remains shockingly low at just 13%, according to the American Cancer Society. Carpizo, a professor of Surgery and Biomedical Genetics at UR Medicine and co-leader of Wilmot’s Genetics, Epigenetics, and Metabolism (GEM) program, has spent years studying why the disease resists treatment. “I routinely see patients who undergo surgery and experience a recurrence despite our best efforts,” he says. “This study brings us closer to understanding how these cancer cells can hide out for long periods—and how to finally target them.”
The Immune System’s Blind Spot
Most cancers are visible to the immune system, which can be rallied with immunotherapies to attack tumors. But pancreatic cancer is different. It has a unique ability to disguise itself, making it invisible to the immune system’s killer T cells. Carpizo’s team found that Dec2, a gene with previously unknown functions in cancer, plays a central role in this deception. The gene regulates molecules on the surface of tumor cells, essentially cloaking them from immune detection. When researchers disabled Dec2 in laboratory models, the immune system could finally “see” and attack the cancer cells.
This discovery is particularly significant because it identifies Dec2 as a potential new target for therapy. If drugs could be developed to block its activity, it might make pancreatic cancer cells visible to the immune system once again, opening the door for more effective immunotherapies.
A Matter of Time
The team also uncovered a surprising twist: Dec2 follows a daily rhythm, rising and falling in activity within cancer cells throughout the day. This circadian pattern means that the immune system’s ability to detect and attack pancreatic cancer cells may depend on the time of day. Carpizo explains that this finding provides a biological explanation for why some immunotherapies seem to work better when given in the morning than in the evening.
“Our research shows that the time of day matters when it comes to immunotherapy,” Carpizo says. “This could help optimize treatment schedules and improve outcomes for patients.”
Vaccines and the Half-Response Challenge
Recent attention has focused on an experimental mRNA vaccine for pancreatic cancer, tested in a small clinical trial at Memorial Sloan Kettering with 16 patients. The vaccine, which uses a patient’s own tumor mutations to train the immune system, showed promise: eight of the participants generated a strong immune response and remained alive for several years. However, the other eight did not respond at all.
Carpizo is concerned about those who did not benefit from the vaccine. “Vaccines like this depend on T cells being able to seek out and destroy cancer cells,” he says. “If Dec2 is interfering with that process, it may explain why half the patients didn’t respond. Targeting Dec2 could be an alternative solution.”
From Lab to Clinic
Carpizo’s team designed a laboratory model using mice to mimic how pancreatic cancer progresses in humans. This model allows them to study the cancer microenvironment—the complex interplay of tissues and cells around tumors that make it easier for cancer to survive and grow. Their work was supported by a pilot grant from Wilmot and the National Cancer Institute, and the findings have already sparked plans for a new clinical trial at Wilmot Cancer Institute, expected to begin early in 2024.
The next step is to translate these discoveries into treatments for patients. Carpizo and his colleagues are optimistic that understanding Dec2 and its role in immune evasion could lead to more effective therapies, including combination treatments that target both the tumor and the gene’s circadian rhythm.
This article is for informational purposes only and is not intended as medical advice. Always consult with a healthcare provider for personalized medical guidance.
As researchers continue to unravel the mysteries of pancreatic cancer, each new clue brings us closer to better treatments and, better outcomes for patients. For updates on clinical trials and research, visit the Wilmot Cancer Institute and the National Cancer Institute.
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