Neutrophil-derived complement factor P induces cytotoxicity in basal-like cells via caspase 3/7 activation in pancreatic cancer

Abstract

Due to profound heterogeneity within stromal immune tumor microenvironment (TME), pancreatic ductal adenocarcinoma (PDAC) remains a hard to treat disease, with the lowest 5-year survival below 10%. Large-scale transcriptomic analysis has revealed two main, clinically relevant PDAC signatures: therapy responsive ‘Classical’ subtype with better prognosis, and poorly-differentiated Basal-like with poor prognosis. It has also become evident that the cellular and humoral components in the immune TME considerably influence the outcome of tumorigenesis. Complement system, a potent humoral innate immune mechanism, also forms a part of this immune TME. In addition to the regular production of various complement components in the liver, certain infiltrating immune cells such as macrophages, dendritic cells and neutrophils, can produce a few complement components locally at the site of infection and inflammation including TME, and modulate tumorigenic outcomes. Neutrophils are the most prevalent innate immune cells in the PDAC TME; however, its role has been attributed as either pro-tumorigenic or anti-tumorigenic. Neutrophils, when stimulated or under stress, are capable of releasing their secretory granules that also contain the only known up-regulator of the complement alternative pathway, Complement Factor P (CFP) or properdin. Properdin can not only facilitate alternative pathway activation by stabilising the C3 convertase, but also act as a pattern recognition receptor on its own and modify inflammatory response. Here, by combining multicenter transcriptome analysis of PDAC patient tumors, single-cell-RNA-seq analysis, preclinical mouse models and human PDAC specimens, we show that properdin expression and neutrophil surveillance are linked to better prognosis in PDAC patients. Furthermore, properdin expression is substantially higher in well-to-moderately differentiated Classical subtype compared to the highly aggressive basal-like PDAC tumours. Mechanistically, exogenous properdin binds to the cell membrane and activates caspase 3/7 to induce apoptosis in basal-like PDAC cells. Together, these findings suggest that the complement protein, properdin, could be a favorable prognostic factor and exhibit anti-tumorigenic functions in PDAC.