Pancreatic adenocarcinoma (PAAD), the 3rd leading cause of cancer death in Western societies, is a lethal cancer, with a median survival less than 6 months, and only 10% beyond 5 years. Initial symptoms are often benign and there are no early detection biomarkers, resulting in more than 80% of patients presenting with locally advanced or metastatic disease. Combination chemotherapy is provided to these patients with palliative intent; however, most do not respond. There is an urgent need to better understand the oncogenesis of PAAD to identify new treatment opportunities in addition to predictive biomarkers to improve treatment selection, particularly as novel targeted therapies emerge.
Dysregulated activation of the immune system has emerged as a driver of chronic pancreatic inflammation and subsequent PAAD formation. However, we have a poor understanding of the cellular ecosystems within PAAD. In a well-studied pre-clinical murine model of pancreatic cancer, we identified a significant increase in neutrophils within the tumour microenvironment that unexpectedly, produce pro-tumorigenic and pro-fibrotic cytokines.
The potential of modifying the innate immune response to treat PAAD remains unexplored. Patient stratification on the basis of integrated genotypic-immunophenotypic analyses will be necessary for successful clinical trials and tailored precision immunological therapies. We have revealed, using the diagnostic full blood count data for pre-treatment patients available within our PURPLE clinical registry, that a high neutrophil-to-lymphocyte ratio (NLR) predicts poor overall survival (OS; N=1511 patients, median OS 12.8 vs 5.5 months). This provides an opportunity to predict ‘immune health’ at minimal inconvenience or cost to the patient. We also explored the composition of neutrophils within the systemic circulation of PAAD patients and identified a subset of proinflammatory CD98+ neutrophils as significantly increased compared to healthy controls. In order to explore where these, and other, neutrophil populations are localised within a PAAD tumour relative to other stromal cell types we will employ emerging spatial technologies. We will determine prognostic associations by extracting the patient's clinical history from our unique PURPLE translational registry. These studies will better define the molecular mechanisms underlying the innate immune response in PAAD and may identify signalling networks that are therapeutically tractable.