Daria Esterházy, PhD

Is the immune suppressive nature of the small intestine to blame for a deadly pancreatic cancer?

Although pancreatic-ductal adenocarcinoma (PDAC) is relatively rare, treatment has not improved in the last 30 years, and it remains one of the most fatal cancers. It is an aggressive cancer that is resistant to both chemotherapy and immunotherapy. Additionally, researchers and clinicians have noticed that the disease is linked to environmental factors such as toxins, metabolic stress and lifestyle. The stomach and intestines are highly subject to these environmental factors and your intestine has an immune system programmed to deal with them. Additionally, the pancreas has a number of unique connections with the upper small intestine (the duodenum), including shared blood vessels, lymph nodes and pancreatic juice ducts, which may allow the upper small intestine to affect the stress tone of the pancreatic tissue.

Dr. Esterházy proposes to test her hypothesis that these unique connections between the pancreas and the upper small intestine serve as routes by which the duodenum sets the state of the immune system in pancreatic tissue. She suggests that two branches of the pancreatic immune system could be influenced by the duodenum: The “adaptive immune system”, implicated in cancer cell specific killing and our strongest immunological memory, which is instructed in lymph nodes, and the tissue resident “innate immunity” that every pancreatic cell and special innate immune cells possess, and is instructed more by environmental cues. With this Cancer Research Foundation Young Investigator Award, Dr. Esterházy and her team will address the former by examining the effect of changes within the draining lymph nodes on pancreatic tumor immunity and tumor progression. Due to its shared lymph node drainage with the immunosuppressive duodenum, the pancreas may also become overly immune suppressive through this relationship and thus unable to recognize the threat of cancer and mount an immune-driven antitumor response. To address the latter, they will investigate innate immune and stress responses in pancreatic tissue when the intestinal system is disturbed with changes in gut bacteria or dietary fat content, and examine the relationship between the duodenal and pancreatic microbiome both ex vivo and in a mouse model of PDAC.

Understanding the consequences of intestinal changes on the adaptive and innate pancreatic tumor immune system may inform new treatment options that harness the unique connections of these two organs. Moreover, this work will lay the foundation for developing therapeutic duodenal microbiomes and investigating the possibility of using changes to the intestinal systems, usually by therapies taken by mouth, to target the pancreatic immune system and allow immunotherapy to be more effective.

2022 Final Report

Pancreatic-ductal adenocarcinoma (PDAC) is a devastating disease accounting for 3 % of all cancers in the United States with a 5-year survival rate of less than 10 %. The only cure is surgery upon early detection, as PDAC is unresponsive to chemo- and immune checkpoint therapy. Thus there is an urgent need to better understand the biology of the etiology, aggressiveness and apparently immunosuppressed nature of PDAC in order to devise more efficient therapeutic strategies. The objective of this grant was to test the hypothesis that unique connections between the pancreas and the duodenum through shared vessels and tolerance-promoting lymph nodes are responsible for both, environmental triggers of PDAC and its immunosuppressed nature.

1.) Impact of vessel sharing between pancreas and gut on pancreatic immunity.
With support of the CRF YI grant we discovered that all intestinal infections that elicit a response involving a particular cytokine, called IL-22, will activate an inflammatory response in the pancreas as well-despite the fact that the infectious agent does not spread to pancreas, indicating that IL-22 in the common vasculature is the mediator. Pathogens that can do this are fungi and bacteria. This inflammatory pancreatic response can lead to pancreatitis, which is a pre-requisite for PDAC. Thus, we have uncovered one unifying molecular mechanism by which the gut microbiome impacts susceptibility to PDAC.

2. Impact of lymph node sharing between pancreas and gut.
Lymph nodes (LNs) are typically sites where the adaptive immune system is instructed in a manner appropriate for the particular tissue drained. While most organs are thought to have their own LN, it turns out many of those of the pancreas are shared with either the liver or the upper small intestine, the duodenum. With support of the CRF YI award we mapped which LNs are shared in mice, and discovered that this sharing has major consequences for pancreatic immunity: In LNs shared with the liver, pancreatic self-antigens are reacted to in a slightly pro- inflammatory way, but in those shared with the duodenum an immunosuppressive reaction to pancreas is elicited. This predicts that, due to this sharing, the body will be tolerized to pancreatic tumor antigen, compromising, if not preventing, the effectiveness of immunomodulatory therapies such as checkpoint inhibitors. We took the studies a step further and interrogated what happens to pancreatic antigen handling if we render the gut draining LNs more pro-inflammatory, e.g. through a viral infection, and excitingly discovered that now we can change the reaction to being pro-inflammatory.

Taken together, the discoveries pave the path for devising targeted strategies to manipulate the pancreatic immune system through interventions in the gut, thus changing the course of PDAC.

Is the immune suppressive nature of the small intestine to blame for a deadly pancreatic cancer?

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