Pancreatic cancer patients may benefit from future precision treatments as a new study shows how some tumours may potentially be more susceptible to macrophage-based therapies.
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, with very few effective treatment options. A new study analysing immune cells from pancreatic tumours and the blood of 12 patients—along with data from other studies—reveals that the immune environment in these tumours is highly complex.
The study, published in Nature Communications, was led by Associate Professor Rachael Bashford-Rogers at the University of Oxford and Associate Professor Shivan Sivakumar from the University of Birmingham who conducted much of the early research at the Kennedy Institute, University of Oxford. It provides the most detailed immune map yet for pancreatic cancer. The researchers found that some pancreatic cancer patients have adaptive-enriched tumours, where the immune system mounts a stronger response, with more B and T cells attempting to fight the cancer. Others have myeloid-enriched (ME) tumours, dominated by immunosuppressive myeloid cells that can weaken the body’s ability to attack the tumour. Patients with ME tumours tend to have worse survival outcomes.
Professor Rachael Bashford-Rogers, senior author of the study said: ‘This research helps explain why current immunotherapies have largely failed in pancreatic cancer and offers a roadmap for developing new treatments tailored to the immune makeup of each patient’s tumour. By combining multiple types of data and advanced computational tools, this study provides valuable insights that could guide future clinical trials and improve survival for pancreatic cancer patients.
‘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 in some patients, and in others, depleting suppressive immune cells to enhance immune-based treatments.’
Dr Shivan Sivakumar, lead author of the study said: ‘Pancreatic cancer is a tumour that does not respond to existing immunotherapies (checkpoint inhibitors). A basis for this is that there is not the same immunogenic reaction to the tumour 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 which immune cells are present in pancreatic cancer and has let us see how the tumour 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.’
Study insights could lead to more effective treatments
The study found that patients with a stronger adaptive immune response also showed certain characteristics of activation in their T and B cell populations, indicating a more active immune attack on the tumour. Through the author’s novel multi-omics approaches, the researchers discovered that certain CD8+ T cells (killer T cells) were highly activated and expanded within these tumours. These tumours may benefit from boosting immune activation, such as cancer vaccines or therapies targeting T cell exhaustion.
On the other hand, patients with a myeloid-enriched tumours had a more immunosuppressive tumour environment, meaning that the immune system is less likely to be able to “see” the tumour cells and kill them. They found that regulatory T cells (Tregs) were highly expanded and suppressing the immune response to these tumours. These tumours may benefit from targeting Tregs (e.g., CCR8 inhibitors) or reprogramming myeloid cells to support the immune response. Alternatively, potential drug targets to overcome immune suppression and improve T cell infiltration into tumours could be prioritised for these patients, such as those targeting TIGIT/PVR, SIRPA/CD47, and CCR8. Blocking these pathways may help turn a “cold” tumour (which the immune system struggles to attack) into a “hot” tumour that responds better to treatment.
Finally, an analysis of patients from a clinical trial (APACT) revealed that those with myeloid-enriched tumours had shorter survival times than those with adaptive-enriched tumours, reinforcing the idea that boosting the adaptive immune response could improve outcomes.
These insights could help guide the development of more effective treatments for pancreatic cancer by making the immune system better at recognising and fighting tumours.