Pancreatic cancer is deadly; only about 10% of patients live over five years after they are diagnosed. Patients can be treated in several ways, including with chemotherapy and surgery. Immunotherapies that are known as checkpoint inhibitors do not usually work well, but T cell therapies that aim to attack pancreatic tumors show some potential. Now, scientists have identified cryptic peptides, or small bits of proteins that are generated from parts of the human genome that are not thought to usually produce proteins.
This study revealed around 500 cryptic peptides that are thought to only be produced in pancreatic tumors, making them an excellent target for therapies. The investigators also engineered T cells that targeted these cryptic peptides. In a cell model, the T cells attacked the tumor organoids crated from patient cells. They were also able to reduce the growth of tumors in a mouse model. The work has been reported in Science.
"Pancreas cancer is one of the most challenging cancers to treat. This study identifies an unexpected vulnerability in pancreas cancer cells that we may be able to exploit therapeutically," said Tyler Jacks, a Professor at MIT, among other appointments.
With a method called immunopeptidomics, the peptides that are found on the surfaces of cells are isolated, and then identified with mass spectrometry. Researchers showed that antigens that were present on the tumor organoid cells were cryptic antigens.
Cryptic peptides or antigens are known to be produced in some tumors, but this work may be the first to show that pancreatic tumors also make them. After analyzing organoids, which are cellular models that in this case were made from pancreatic cancer patient cells, they investigators identified an average of about 250 cryptic peptides in each organoid. In all, roughly 1,700 cryptic peptides were found.
The scientists then checked healthy tissues whether any of the 1,700 cryptic peptides were also present on normal cell surfaces. This revealed that about two-thirds are found in one type of healthy tissue or more, leaving about 500 that seem to only be on pancreatic cancer cells.
"Those are the ones that we think could be very good targets for future immunotherapies," said senior study author Dr. William Freed-Pastor, an assistant professor at Harvard Medical School, among other apppointments.
Though, the results of the effort are still years away, the Freed-Pastor lab is now working on a vaccine that could target some of the cryptic antigens, and may help patients' T cells to attack any tumors that carry those antigens.
Sources: Massachusetts Institute of Technology, Science