Pancreatic cancer immune landscape reveals opportunities for personalized therapies

Pancreatic cancer patients may benefit from future precision treatments as a new study shows how some tumors may potentially be more susceptible to macrophage-based therapies.

The study which is published in Nature Communications was led by Associate Professor Shivan Sivakumar from the University of Birmingham and Associate Professor Rachael Bashford-Rogers at the University of Oxford and provides the most detailed immune map for pancreatic cancer. The findings suggest that some tumor cells are more likely to be infiltrated by T cell treatments, while others had myeloid cell infiltration. This means that cells such as macrophages could be suitable for future immunotherapeutic treatments in some cases.

Using cells from twelve patients, the research team created a single cell map of tumor infiltrating immune cells and peripheral immune cells, coupled with gene expression, single cell TCR and BCR sequencing and identifying proteins expressed on these cells. The team then verified their findings using two other large publicly available pancreatic cancer datasets.

Dr. Shivan Sivakumar, Associate Professor of Oncology from the University of Birmingham and lead author of the study said:

"Pancreatic cancer is a tumor that does not respond to existing immunotherapies (checkpoint inhibitors). A basis for this is that there is not the same immunogenic reaction to the tumor that exists in other cancers. We therefore mapped out how the immune system is constructed in pancreatic cancer patients. This has helped us understand with a high degree of confidence what immune cells are present in pancreatic cancer and let us see how the tumor evades the immune system.

"We demonstrate the need for trials to assess changes in immune infiltration over time. Collectively our data provides a foundation for understanding the failure of immunotherapy in pancreatic cancer with an avenue for designing novel therapeutics and tailored interventions.

We have uncovered distinct immune environments in pancreatic cancer, revealing new therapeutic opportunities to improve outcomes for this deadly disease. By leveraging single-cell multi-omics and novel computational approaches, this study identifies potential strategies such as boosting certain cell responses, and depleting suppressive immune cells to enhance immune-based treatments."

Rachael Bashford-Rogers, Associate Professor of Molecular and Cellular Biochemistry from the University of Oxford and senior author of the study

Potential therapeutic targets identified

The study has also uncovered the important understanding about the role of specific immune cells, such as activated regulatory T cells (Tregs) and B cells, in the immunopathology of this disease. The team have found that these cells could help to distinguish patients that may benefit from targeted treatments that activate the existing immune response in the tumor area (rich in B and T cells) versus those that have a highly suppressive tumor environment (rich in myeloid cells). Tackling these cells would play an important therapeutic strategy in the future against this disease.

With this understanding, potential targets have been identified with more weight being given to the target TIGIT that was previously identified as a target of interest in this disease and now this work also suggests that CD47 can be targeted too. The work also suggests strategies to boost B cell responses, target immunosuppressive macrophages and deplete activated intratumoral Tregs will be of benefit to different subsets of patients, and these are now fertile areas to investigate.

Pancreatic cancer is among the deadliest cancers globally, with a survival rate beyond 10 years of less than 1% in England (2013-2017). It is often only when the cancer has reached an advanced stage that physical symptoms appear, at which point it becomes more difficult to treat.

Dr. Sivakumar said:

"As an honorary consultant in medical oncology focused on pancreatic, liver and biliary tract cancers, I am perhaps more familiar than most with the devastating nature of this disease. According to the charity Pancreatic Cancer UK, it is the 5^th biggest cancer killer in the UK, with 9,000 deaths every year. Pancreatic cancer also has the lowest survival rates of all common cancers, with a five-year survival rate of less than 7%.

"Sadly, pancreatic cancer is typically diagnosed at a late stage, when curative surgery is no longer an option. The problem is exacerbated by the fact that for the 'lucky' 1 in 10 who are eligible for surgery, the recurrence rate of pancreatic cancer after surgical treatment is over 80%.

"We are currently running the mRNA vaccine study for pancreatic cancer to see if this can prevent recurrence in Birmingham and have two further studies imminently opening in this disease.. Working closely with the private sector who play a key role in drug development, and armed with the insights we have gained from this study and others, we are now also constructing our own investigator initiated studies to help see if we can use precision immunotherapeutics to help provide good treatment options for these patients.

"Any potential breakthroughs in pancreatic cancer treatment are therefore so important. With over 150 pancreatic cancer operations happening each year here in Birmingham, it's a fantastic place to do translational research that will ultimately impact on patient care and outcomes."