MIT and Dana-Farber scientists have uncovered hundreds of cryptic peptides unique to pancreatic tumors—unveiling new targets for powerful, customized T cell therapies and vaccines.
Key Points at a Glance
- Researchers identified 500 cryptic peptides exclusive to pancreatic tumors
- T cells were engineered to attack these targets and slowed tumor growth in mice
- This is the first time cryptic peptides have been targeted in pancreatic cancer
- The findings may lead to vaccines and T cell therapies within several years
- Potential to significantly improve outcomes in one of the deadliest cancers
Pancreatic cancer is one of the most lethal malignancies, with a five-year survival rate stuck at around 10%. It is a disease so elusive that even advanced immunotherapies often miss the mark. But a new study from MIT and Dana-Farber Cancer Institute may have cracked open a hidden vulnerability—a molecular backdoor into pancreatic tumors that has gone unnoticed until now.
The breakthrough centers on cryptic peptides—protein fragments derived from genomic regions previously thought not to encode proteins at all. Using advanced mass spectrometry techniques, researchers identified about 1,700 of these cryptic peptides in pancreatic tumor samples. Strikingly, roughly 500 of them were found exclusively in tumor cells, making them attractive targets for immunotherapies that rely on T cells to hunt and kill cancer.
“These are unexpected targets,” says Tyler Jacks, a senior author of the study and Professor of Biology at MIT. “And they may be exactly what we need to go after pancreas cancer with more precision.”
These peptides are called “cryptic” for a reason—they’re typically hidden from view. But using a powerful method called immunopeptidomics, researchers extracted and identified the peptides presented on the surface of pancreatic tumor cells grown in lab-based organoids. The analysis revealed that these cryptic peptides form the dominant class of novel antigens in these tumors, something not previously observed in pancreatic cancer.
The researchers didn’t stop at identification. They selected 30 of the most tumor-specific peptides and exposed them to naive T cells to see if they could provoke an immune response. A dozen of them did. Next, they engineered T cells to express receptors specifically designed to latch onto these peptides. When introduced into lab-grown tumor organoids—and later, into mice implanted with those organoids—the T cells successfully attacked the tumors and slowed their growth.
While the tumors weren’t completely eliminated, the significance of this finding cannot be overstated: it marks the first time T cells engineered to recognize cryptic peptides have been shown to kill pancreatic tumor cells.
“Immunotherapy hasn’t worked well in pancreatic cancer because it’s hard to find the right targets,” says co-senior author William Freed-Pastor of Dana-Farber. “Now we have a new and abundant set of targets that exist only on the cancer cells.”
This discovery has potential beyond T cell engineering. Freed-Pastor’s lab is already working on a vaccine that could prime the immune system to attack tumors based on these peptides. The idea is to bundle the most frequently expressed cryptic antigens into a single therapeutic cocktail, teaching the body to recognize and destroy tumor cells before they take hold or grow.
The approach could also lend itself to next-generation antibody therapies, like T cell engagers that physically bring immune cells into contact with tumor cells by binding to one on each side.
Pancreatic cancer has long resisted the immunotherapeutic revolution seen in other cancers like melanoma or lung cancer. This study suggests that might be changing. By revealing a trove of previously undetected targets, scientists may have finally pried open a therapeutic window in a disease that has stubbornly resisted all others.
While any clinical applications are still years away, this work lays the essential groundwork. In a field where time is precious, finding even one viable new target can spark hope. Finding 500? That’s a revolution waiting to happen.
