Patients with pancreatic cancer may find promise in future tailored treatments as recent research suggests that certain tumors may be more responsive to therapies based on macrophages.
A new study published in Nature Communications, led by Associate Professor Shivan Sivakumar from the University of Birmingham and Associate Professor Rachael Bashford-Rogers from the University of Oxford, has produced a comprehensive immune map for pancreatic cancer. Their findings indicate that some tumor cells are more prone to being penetrated by treatments involving T cells, while others are infiltrated by myeloid cells, suggesting that macrophages could play a role in future immunotherapy options.
By examining cells from twelve patients, the research team constructed a detailed map of immune cells infiltrating the tumors and their corresponding peripheral immune cells. They also analyzed gene expressions, single-cell T-cell receptor (TCR) and B-cell receptor (BCR) sequencing, and identified proteins present on these cells. Their results were validated using two other large publicly available data sets on pancreatic cancer.
According to Dr. Shivan Sivakumar, Associate Professor of Oncology at the University of Birmingham and lead author of the study:
“Pancreatic cancer typically does not react to current immunotherapies, such as checkpoint inhibitors. This limited response is partly due to the tumor’s lack of immune reactions compared to other cancers. We meticulously mapped the structure of the immune system in pancreatic cancer patients, which has significantly enhanced our understanding of the immune cells present and how tumors manage to evade immune detection.”
“Our research underscores the necessity of conducting trials that evaluate changes in immune cell infiltration over time. Together, our findings lay the groundwork for understanding why immunotherapy often fails in pancreatic cancer and pave the way for developing new therapeutic strategies and personalized treatment approaches.”
Senior author Rachael Bashford-Rogers, Associate Professor of Molecular and Cellular Biochemistry at the University of Oxford, remarked:
“We have discovered unique immune environments in pancreatic cancer, unveiling new therapeutic opportunities to enhance treatment outcomes for this challenging illness. Using innovative single-cell multi-omics and computational methods, this study pinpoints potential strategies such as enhancing specific cell responses and reducing suppressive immune cells to improve immune-based therapies.”
Identifying Possible Therapeutic Targets
This study has offered crucial insights into the roles of particular immune cells, like activated regulatory T cells (Tregs) and B cells, in the disease’s immunopathology. The team has determined that these cells may help differentiate patients who could gain from targeted treatments aimed at activating the immune response in tumor areas rich in B and T cells versus those with a suppressive tumor environment filled with myeloid cells. Addressing these immune cells is likely to be a vital therapeutic strategy moving forward in combatting the disease.
With these insights, potential therapeutic targets have surfaced, particularly emphasizing TIGIT, previously recognized as a target of interest. Additionally, this research suggests that CD47 could also be a viable target. Strategies aimed at enhancing B cell responses, combating immunosuppressive macrophages, and depleting activated Tregs within tumors are likely to benefit various subsets of patients, offering fertile grounds for further exploration.
Pancreatic cancer is one of the most lethal cancers worldwide, with a 10-year survival rate of less than 1% in England between 2013 and 2017. Symptoms often manifest only after the disease has progressed to advanced stages, making treatment more challenging.
Dr. Sivakumar added:
“As a consultant in medical oncology focusing on pancreatic, liver, and biliary tract cancers, I have a deep understanding of the severe impact of this disease. According to the charity Pancreatic Cancer UK, it ranks as the 5th leading cause of cancer deaths in the UK, with approximately 9,000 fatalities each year. Furthermore, pancreatic cancer has the lowest survival rates of all common cancers, with a five-year survival rate below 7%.
“Regrettably, pancreatic cancer is often diagnosed at an advanced stage, at which point curative surgery is no longer viable. This issue is compounded for the ‘fortunate’ 1 in 10 patients who are eligible for surgery, as the recurrence rate post-surgery exceeds 80%.
“We are currently conducting an mRNA vaccine study aimed at preventing recurrence in pancreatic cancer in Birmingham, and we plan to launch two additional studies soon. Collaborating closely with the private sector, which plays a vital role in drug development, and equipped with insights from this and other studies, we are initiating our own investigator-led studies to explore the potential of precision immunotherapeutics and offer improved treatment options for patients.”
“Any advancements in the treatment of pancreatic cancer are incredibly important. With over 150 pancreatic cancer surgeries performed annually in Birmingham, it is an excellent location for conducting translational research that can ultimately enhance patient care and outcomes.”
