New research unveils role of innate immune system in pancreatic cancer

Researchers from Adelaide University have demonstrated that blocking a specific immune system gene can reduce pancreatic cancer tumor formation.

Pancreatic cancer is predicted to be the second most lethal cancer in western countries by 2030, and is associated with a low overall five-year survival rate of approximately 13%, in part because the cancer is often advanced by the time it is diagnosed.

Current standard-of-care chemotherapy, and more recently immunotherapy treatments, are also largely ineffective.

Professor Brendan Jenkins, Program Head of Tumor Inflammation and Immunotherapy at the South Australian immunoGENomics Cancer Institute (SAiGENCI), and Dr Joshua Chey, have shown that the gene which makes the ASC protein can have a significant impact on tumor formation in pancreatic cancer models.

In a multi-layered study, the research first identified upregulation of the ASC protein in patient pancreatic cancer tissue, before moving to a pre-clinical model to further investigate its impact in the progression of cancer.

The findings were published in the journal Nature Communications.

"More than 90% of cases present as pancreatic ductal adenocarcinoma (PDAC), which we know is driven by genetic alterations in the organ coupled with dysregulated innate immunity that triggers tumor- promoting chronic inflammation," said Professor Jenkins.

"But, until now, there wasn't much known about the innate immune molecular regulators as targets in PDAC.

"We have been able to show the inflammasome adaptor protein ASC indicates poor survival outcomes in patients, and that it promotes PDAC by acting as a molecular bridge between innate immunity and energy metabolism within cancer cells.

"In our pre-clinical model, we showed that deletion of the gene for ASC, or using a small inhibitor (nanobody derived from alpacas) against ASC protein, significantly reduced the formation of pancreatic tumors. This provides the rationale to therapeutically target ASC in cancers."

The appearance of ASC has long been associated with inflammatory diseases like gout and arthritis." 

Dr Joshua Chey, First Author, South Australian immunoGENomics Cancer Institute (SAiGENCI)

"In solid cancers it can be hard to penetrate fibrous tissue surrounding cancer cells, but we found the use of small nanobodies against ASC are able to penetrate and target the ASC protein in our preclinical disease model.

"This new inhibitor drug has had success with models of inflammatory conditions, but this was the first time it has been demonstrated to have anti-cancer activity.

"We can see this strategy of blocking ASC working in combination with existing therapies, to give patients better responses and improve the long-term survival rate."