New Research Reveals Why Pancreatic Cancer Is Hard to Treat

Researchers at University of Rochester Medicine have identified a genetic mechanism that helps pancreatic cancer cells evade the immune system, offering new insights into why the disease is notoriously difficult to treat and often recurs after surgery.

The study, published in the journal Developmental Cell, focuses on the role of a specific gene called Dec2. The findings suggest that this gene acts as a disguise, preventing the body’s killer T cells from detecting and destroying tumor cells.

Pancreatic cancer often develops undetected for years before symptoms appear, and it remains one of the most lethal malignancies. According to Darren Carpizo, a surgeon-scientist and member of the Wilmot Cancer Institute who led the study, the five-year survival rate for the disease is only 13%.

I routinely see patients who undergo surgery and experience a recurrence despite our best efforts, and that is disappointing. Our new study brings us another step closer to understanding how these pancreas tumor cells can hide out for long periods of time, and how to target them.

Darren Carpizo, surgeon-scientist and member of the Wilmot Cancer Institute

The Role of the Dec2 Gene

The research team discovered that Dec2 regulates a molecule on the surface of tumor cells. By manipulating this molecule, the gene effectively hides the cancer cells from the immune system’s killer T cells.

In laboratory settings, researchers tested the impact of removing this gene. When the team knocked out Dec2, the immune cells were able to locate and target the pancreatic cancer cells, suggesting that Dec2 could serve as a viable target for future therapies.

This discovery addresses a significant hurdle in oncology: the failure of many modern immunotherapies in pancreatic cancer. While some immunotherapies have succeeded in other cancer types by rallying the immune system to attack the disease, they have largely remained ineffective against pancreatic tumors due to the cancer’s unique ability to evade immune detection.

Circadian Rhythms and Treatment Timing

A particularly novel aspect of the study is the discovery that Dec2 operates on its own sleep-wake cycle, or circadian rhythm. The levels of the gene fluctuate within pancreatic cancer cells throughout the day.

The researchers demonstrated that the time of day significantly impacts the ability of T cells to kill pancreatic cancer cells. This provides a biological basis for clinical observations regarding the timing of immunotherapy administration.

Carpizo noted that clinicians have observed that immunotherapy administered in the morning appears to be more effective than when given in the evening.

Implications for mRNA Vaccines

The findings also have implications for emerging treatments, such as an experimental mRNA vaccine for pancreatic cancer. In a small clinical trial conducted at Memorial Sloan Kettering involving 16 patients, the vaccine improved survivorship for half of the participants.

Specifically, eight patients generated an immune response that allowed them to remain alive for several years. However, the other eight patients did not respond to the vaccine.

Carpizo suggests that the activity of Dec2 might explain why 50% of the patients in that trial did not respond, as the vaccine relies on T cells to seek out and destroy cancer cells—a process Dec2 is designed to block.

Vaccines like this one depend on T cells being able to seek out and destroy cancer cells. Our research has important implications for this, because if the actions of Dec2 will not allow the vaccine to work properly it may explain why 50% of the patients didn’t do well. Targeting Dec2 may be an alternative solution.

Darren Carpizo, professor of Surgery and of Biomedical Genetics at URochester Medicine

Research Methodology and Support

To achieve these results, the research team utilized a specialized laboratory model using mice designed to mirror the progression of pancreatic cancer in humans. This model allowed the team to study the cancer microenvironment, which is the complex interaction of tissues and cells surrounding tumors that often helps the cancer survive.

The research was supported by a pilot grant from the National Cancer Institute and the Wilmot Cancer Institute. Carpizo also serves as the co-leader of Wilmot’s Genetics, Epigenetics, and Metabolism (GEM) basic research program.