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.