18 June 2021

Promising study on the immune system in pancreatic cancer

New study by Erler group explores the immune system’s function in pancreatic cancer and finds that an existing therapy can be used to suppress pancreatic tumor development in pre-clinical mouse models. The research was supported by the Danish Cancer Society.

Janine Erler, Jan Strøbech & Sebastian Rune Nielsen
From left: Professor Janine Erler (senior author) and joint first authors PhD student Jan Strøbech & postdoc Sebastian Rune Nielsen

Pancreatic cancer is a devastating disease that is often detected at an advanced stage, which makes it very difficult to treat, and new therapeutic options are needed. Researchers at Biotech Research and Innovation Centre (BRIC) at the University of Copenhagen have now discovered a compound that could offer a new therapeutic option for treatment of pancreatic cancer.

The researchers have found that lorlatinib, which is already approved for the treatment of specific types of lung cancer, can suppress the development of pancreatic cancer in pre-clinical mouse models. Even though there is a long way from pre-clinical mouse models to treatment of patients, the results are encouraging according to the first author of the study, postdoc Sebastian Rune Nielsen.

"It is difficult to achieve a good response to treatment in mouse models of pancreatic cancer, but when we treat with lorlatinib we are able to suppress tumor development, and when we combine the drug with anti-PD-1 immunotherapy, we achieved an even better response with the combination," he explained.

He is complemented by senior author Janine Erler, professor at BRIC.

"It’s encouraging that the drug is already approved for treatment of lung cancer. That means it has passed initial phases of clinical trials and that it is well tolerated by patients", says Janine Erler.

Immature immune cells

Sebastian Rune Nielsen focuses on the role of the immune system in pancreatic cancer. He explains that this cancer type is characterized by a high degree of immune cell infiltration by cells from the innate part of the immune system, among them neutrophil granulocytes. They are produced in the bone marrow and serve as the immune system’s frontline soldiers.

"Neutrophil granulocytes are supposed to arrive quickly to a site of infection and neutralize the threat to make way for other immune cells that participate in the rebuilding of the infected tissue. But their role seems to be inverted in pancreatic cancer, and they promote rather than fight tumor development", he explains and continues:

"Our hypothesis is that the tumor cells apply pressure to the bone marrow to promote the production of neutrophil granulocytes, which leads to the release of immature cells that are not functioning as they are supposed to. One can say, that pancreatic cancer corrupts the immune system to promote tumor development", explains Sebastian Rune Nielsen. 

Treatment blocks cell signaling

The main goal of the research was to find a way to modify the neutrophil granulocytes to make them fight the cancer rather than support its growth, continues Sebastian Rune Nielsen.

By searching through the scientific literature, the researchers found the drug lorlatinib. It is a tyrosine kinase inhibitor that can block a specific signaling pathway in the cells, FES, which the researchers found was activated in the neutrophil granulocytes by the cancer cells.

"We demonstrate in our experiments that lorlatinib blocks the signal that FES was supposed to send resulting in suppression of the neutrophil granulocytes", explains Sebastian Rune Nielsen and continues:

"We demonstrate that treatment with lorlatinib reduces the production and release of neutrophil granulocytes from the bone marrow, which leads to reduced infiltration in pancreatic tumors. Our results also demonstrate that we can achieve better response to immunotherapy, when we combine lorlatinib with immunotherapy, so called anti-PD-1 blockade. This combination leads to less neutrophil granulocytes, but more active T cells, another type of immune cell, and further reduction in tumor sizes", he explains.

The right combinations

Sebastian Rune Nielsen hopes that this study can improve the therapeutic options for treatment of pancreatic cancer.

"I believe that research in the future will be aimed at finding the right combinations of drugs. We have not seen good clinical responses to treatment with immunotherapy in pancreatic cancer, but we do get a good response in our experiments when we combine it with lorlatinib. But it is going to take a lot of work and research to find the best combinations", says Sebastian Rune Nielsen.

This new study was published in the recognized scientific journal Nature Communications.

Link to the full study


Postdoc Sebastian Rune Nielsen: Sebastian.Nielsen@bric.ku.dk

Professor Janine Erler: janine.erler@bric.ku.dk