Pancreatic cancer is relatively rare when compared to other cancers, but still the third leading cause of cancer death in the U.S. with one of the lowest survival rates of any cancers. For that reason, much of pancreatic cancer research is dedicated to treating this deadly kind of cancer. Some of that innovative research is happening at IU School of Medicine in the Liu Laboratory for Computational Genomics. Yunlong Liu, PhD, director of the Center for Computational Biology and Bioinformatics at IU School of Medicine, has been conducting recently published research that could impact the development of more effective immunotherapy options for treating pancreatic cancer and even contribute to a vaccine for the disease someday.
Liu’s research team figured out that a type of alternative RNA splicing, called intron-retention (IR), can potentially produce a significant number of new tumor antigens (neoantigens) in pancreatic cancer cells that can attract cancer-killing T cells.
“It’s a new source of antigens that can be used to fight cancers,” said Liu, who is a professor of medical & molecular genetics at IU School of Medicine and a researcher at the Indiana University Melvin and Bren Simon Comprehensive Cancer Center. “We never thought intron-retention was very important because our cells have inherent ways to get rid of RNA molecules with intron retention. But in this process, the cells generate peptide neoantigens that our immune system has never seen before.”
Liu’s graduate student, Chuanpeng Dong, used public domain data from 150 patients with pancreatic cancer and developed a computational approach to estimate the number of patient-specific IR neoantigens and their relationship with patient survival. The study findings, published in February in JCO Clinical Cancer Informatics, a journal of the American Society of Clinical Oncology, offer three potential translational angles that could benefit pancreatic cancer patients with specific tumor cell markers:
- IR-neoantigen load that might serve as a biomarker for selecting those patients who might benefit from cancer immunotherapy. Liu said it could potentially even result in a new kit for patients identified as good subjects for immunotherapy.
- Development of a cancer vaccine based on neoantigen peptides that Liu and his colleagues are currently identifying. It’s too early to suggest that a vaccine is imminent, but Liu said they have provided strong data for scientists in the pharmacology field to pursue.
- Further investigation of RNA splicing inhibitors that may allow patients to benefit from Immune Checkpoint Blockade (ICB) therapy. Liu describes treating cancer cells with a splicing inhibitor as “giving them a little kick,” which triggers them to generate more IR. If that’s the case, he said, they can better engage with a patient’s cancer-killing T cells.
“Cancer cells are smart,” said Liu. “They know how to protect themselves from immune cells.”
And that’s where ICB, a type of immunotherapy, comes into the picture in treating some types of cancer. Immune checkpoint blockades or inhibitors work by helping the patient's own immune system recognize and fight their tumor. Pancreatic cancer does not have a lot of mutations, which are more common in other cancer types where the tumor mutation load is used as one of the eligibility criteria for treatment with new immunotherapy drugs. Thus, ICB has not been routinely used to treat pancreatic cancer patients.
“But this study gave us hints that ICB might actually be beneficial for certain pancreatic patients,” Liu said. “We found that patients with high IR neoantigens have improved overall survival. That triggered us to ask whether patients with high neoantigens and high immune inhibitor signals would benefit from ICB therapy. Because even though the cancer cells display neoantigens, the immune inhibitor molecules act as a shield to protect them from being killed by T cells.”
Liu compared survival in patients with high tumor neoantigens and high inhibitors and compared them with patients showing high tumor neoantigens and low inhibitors.
“We don’t have enough data to say what proportion of pancreatic patients might benefit from immunotherapy,” said Liu. “But it’s the first step in many that will be necessary to know which pancreatic cancer patients can benefit from immunotherapy. We are optimistic. We hope that our findings will benefit a large proportion of pancreatic cancer patients.”