Biologists Discover New Targets for Pancreatic Cancer Treatment
Summary:
A new study from MIT and the Dana-Farber Cancer Institute reveals that cryptic peptides—proteins expressed uniquely in pancreatic cancer cells—could serve as promising targets for T-cell-based therapies aimed at attacking pancreatic tumors.
FULL STORY
Researchers from the Massachusetts Institute of Technology (MIT) and the Dana-Farber Cancer Institute have uncovered a potential new vulnerability in pancreatic cancer cells. They found that a class of molecules called cryptic peptides, which arise from previously unrecognized protein-coding regions of the genome, may be powerful targets for immunotherapies such as T-cell treatments.
While some cryptic peptides can occur in healthy cells, the team identified around 500 that appear to exist exclusively in pancreatic tumors. Importantly, they successfully generated T cells that specifically recognize and attack these peptides—demonstrating reduced tumor growth in patient-derived organoids and mouse models.
“Pancreatic cancer remains one of the most difficult cancers to treat,” said Tyler Jacks, the David H. Koch Professor of Biology at MIT and a member of the Koch Institute for Integrative Cancer Research. “This study reveals an unexpected weakness in pancreatic cancer cells that could be therapeutically exploited.”
The study, published in Science, was co-led by Jacks and William Freed-Pastor, a physician-scientist at Dana-Farber’s Hale Family Center for Pancreatic Cancer Research and an assistant professor at Harvard Medical School. Zackery Ely (PhD ’22) and Zachary Kulstad were the paper’s lead authors.
Cryptic Peptides: Hidden Targets in Cancer
Pancreatic cancer has one of the lowest five-year survival rates—only about 10% of patients survive beyond that point. Current treatments typically combine surgery, chemotherapy, and radiation therapy. Unfortunately, most immunotherapies, such as checkpoint inhibitors, have shown limited success against pancreatic tumors.
However, T-cell therapies—where T cells are engineered to recognize tumor-specific antigens—have shown growing promise in clinical trials. These therapies rely on identifying suitable antigens (protein fragments) that can serve as precise targets.
In this study, the researchers used immunopeptidomics, an advanced technique that identifies peptides displayed on cell surfaces using mass spectrometry. By analyzing tumor samples and organoids from a dozen patients, the team discovered that most novel antigens present in pancreatic tumors were cryptic peptides—marking the first time this has been demonstrated in pancreatic cancer.
On average, each tumor expressed about 250 cryptic peptides, and across all samples, approximately 1,700 were identified.
“As soon as we saw the data, it became clear that cryptic peptides were by far the most abundant novel antigen class,” said Ely.
A further analysis showed that roughly one-third of these peptides were unique to cancer cells, making them potential candidates for highly targeted immunotherapies.
“These are the ones we believe hold the most promise for future treatment development,” added Freed-Pastor.
Engineering T Cells to Target Cancer
To test their therapeutic potential, the team exposed immature T cells to about 30 of the tumor-specific cryptic antigens. Twelve of these successfully activated robust T-cell responses. The researchers then engineered T cells with receptors designed to recognize these antigens.
These programmed T cells were able to destroy pancreatic tumor organoids in vitro and significantly slow tumor growth in mouse models. While complete tumor elimination wasn’t achieved, the findings mark a major step forward in immunotherapy research for pancreatic cancer.
This is the first demonstration that T cells targeting cryptic peptides can effectively kill pancreatic cancer cells.
The team now aims to enhance the effectiveness of these T cells and is exploring vaccine development targeting the same antigens. Such a vaccine could stimulate patients’ immune systems to recognize and attack tumors expressing these cryptic peptides.
Beyond vaccines, these findings could guide the creation of T-cell engager therapies, which use antibodies to link T cells directly to cancer cells for targeted destruction.
Although these treatments are still several years from clinical testing, the discovery provides a new direction for tackling one of the deadliest cancers.
Funding
This research was supported by the Hale Family Center for Pancreatic Cancer Research, The Lustgarten Foundation, Stand Up To Cancer, the Pancreatic Cancer Action Network, the Burroughs Wellcome Fund, a Conquer Cancer Young Investigator Award, the National Institutes of Health, and the National Cancer Institute.
Journal Reference:
- Zackery A. Ely et al. Pancreatic cancer–restricted cryptic antigens are targets for T cell recognition. Science, 2025 DOI: 10.1126/science.adk3487