Chemotherapy may affect the immune system’s ability to attack tumors in patients with pancreatic ductal adenocarcinoma, according to a new study published by Werba et al in Nature Communications.
Background
Pancreatic ductal adenocarcinoma is hard to detect and treat, with a 5-year survival rate of only 12%. A strong immune response in the tumor microenvironment is often critical to shrinking pancreatic tumors.
To spare normal cells, the immune system uses checkpoint molecules like PD-1 on T-cell surfaces to turn off their attack when they receive the right signals. The immune system also recognizes tumors as abnormal, but cancer cells can hijack checkpoints to turn off immune responses. A prominent type of immunotherapy seeks to shut down these checkpoints, thereby making cancer cells visible again to the immune system.
Blocking these off signals—specifically PD-1—is the goal of current immunotherapies designed to fight many cancers, but these agents have so far proven unsuccessful against pancreatic ductal adenocarcinoma.
Study Methods and Results
In the new study, researchers analyzed more than 139,000 tumor cells collected from 27 patients with pancreatic ductal adenocarcinoma—and found a threefold decrease in the production of certain inhibitory checkpoint molecules when comparing 11 patients prior to chemotherapy to 6 others after chemotherapy.
The findings further showed that a second checkpoint—TIGIT—was the most common inhibitory checkpoint molecule in pancreatic ductal adenocarcinoma and was 18 times more available for therapeutic targeting than PD-1 prior to chemotherapy; however, TIGIT was just five times more available after chemotherapy. The researchers indicated that these findings may warrant further studies examining whether immunotherapies that inhibit TIGIT are more effective than immunotherapies that target PD-1 in treating patients with pancreatic ductal adenocarcinoma.
“Our study demonstrates how chemotherapy can have profound effects on the cellular landscape of the tumor microenvironment in [patients with] pancreatic ductal adenocarcinoma,” explained co–senior study author Aristotelis Tsirigos, PhD, Professor of Medicine and Pathology at the New York University (NYU) Grossman School of Medicine and Director of the Applied Bioinformatics Laboratories at NYU Langone Health.
“Importantly, our results suggest that chemotherapy may promote resistance to subsequent immunotherapy in [patients with] pancreatic ductal adenocarcinoma,” stressed co–senior study author Diane Simeone, MD, the Laura and Isaac Perlmutter Professor of Surgery and Professor of Pathology at the NYU Grossman School of Medicine as well as Director of the Pancreatic Cancer Center and Associate Director of Translational Research at the Perlmutter Cancer Center at NYU Langone Health. “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,” she added.
The researchers noted that additional changes following chemotherapy were seen in the number of other immune cells present, the extent of their interactions with each other, as well as decreases in other cancer-associated immune cells—such as fibroblasts and macrophages—that would encourage cancer growth if left unchecked. However, the precise impacts of these molecular changes on treatment remained unclear.
Conclusions
“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,” Dr. Tsirigos concluded.
The researchers reported that additional experiments are currently underway to validate the findings in more patients, and that further research may also be needed to evaluate whether single-cell RNA sequencing of the tumor microenvironment shortly after diagnosis could help guide future treatment decisions.
Disclosure: The research in this study was funded by grants from the National Institutes of Health. For full disclosures of the study authors, visit nature.com.
