Current chemotherapy affects the ability of a patient’s immune system to attack pancreatic tumors, a new study shows.
Led by researchers at NYU Langone Health and its Perlmutter Cancer Center, the work revolves around the immune system and its T cells, which are designed to attack foreign organisms like viruses. To spare normal cells, the system uses “checkpoint” molecules like PD1 on T cell surfaces to turn off their attack when they receive the right signals. Although the body recognizes tumors as abnormal, cancer cells hijack checkpoints to turn off immune responses. A prominent branch of immunotherapy seeks to shut down such checkpoints, making cancer cells “visible” again to the immune system.
Published in the journal Nature Communications on February 13, the study analyzed more than 139,000 tumor cells collected from 27 patients who had pancreatic ductal adenocarcinoma (PDAC), a common type of pancreatic cancer. Because PDAC is so hard to detect and treat, only 12 percent of patients survive longer than 5 years after it is diagnosed. According to researchers, a strong immune response to tumors in the tissue surrounding them is critical to shrinking such tumors in the pancreas.
Among the new findings was a threefold decrease in the production of certain inhibitory checkpoint molecules, based on comparing cells from 11 patients before chemotherapy to 6 others after it. Blocking these off signals, specifically PD1, is the goal of current immunotherapies designed to fight many cancers, although they have so far been unsuccessful against PDAC, according to researchers.
The study showed that a second checkpoint, TIGIT, was the most common inhibitory checkpoint molecule in PDAC. What’s more, before chemotherapy, it was 18 times more available for therapeutic targeting than PD1, but only 5 times more available after chemotherapy. The study authors say that these findings warrant further study, to find out whether immunotherapy focused on TIGIT might be more effective in treating PDAC than immunotherapies that target PD1, also known as programmed cell death protein 1.
“Our study demonstrates how chemotherapy can have profound effects on the cellular landscape of the tumor microenvironment in PDAC,” said study co-senior investigator Aristotelis Tsirigos, PhD, a professor in the Departments of Medicine and Pathology at NYU Grossman School of Medicine and a member of Perlmutter Cancer Center.
“Importantly, our results suggest that chemotherapy may promote resistance to subsequent immunotherapy in PDAC,” said study co-senior investigator Diane M. Simeone, MD, the Laura and Isaac Perlmutter Professor of Surgery in the Department of Surgery at NYU Grossman School of Medicine.
“Further research is needed to determine if, as a result of this potential resistance, chemotherapy needs to be combined with immunotherapy at the start of treating this stubborn and often deadly form of cancer,” added Dr. Simeone, who is also a professor in the Department of Pathology and director of the Pancreatic Cancer Center, part of Perlmutter Cancer Center.
Other changes following chemotherapy were seen in the number of other immune cells present, in how much they interacted with each other, as well as decreases in other immune cells (e.g., fibroblasts and macrophages) that can encourage cancer growth if left unchecked. However, the precise impact of these molecular changes on treatment, the researchers noted, remains to be defined.
Dr. Tsirigos said additional experiments are underway to validate the findings in more patients. He noted that further research is also needed to evaluate whether similarly detailed cell analyses of the tumor microenvironment shortly after diagnosis, through a technique called scRNA-seq, could help guide future treatment decisions.
“As new technologies allow us to see what is happening inside patients at the cellular level, we can start to adjust our evaluations of immunotherapies and possibly how best to use them based on what is actually happening around tumors,” added Dr. Tsirigos, who is also co-director of NYU Grossman School of Medicine’s Division of Precision Medicine.