O148: Unlocking Enhanced Immunity in Pancreatic Ductal Adenocarcinoma: Activins Interplay with CAF-Stroma Mechanisms

Abstract

Abstract SMAD4 is a tumour suppressor gene that is mutated in up to 60% of pancreatic ductal adenocarcinoma (PDAC) tumours. Activins are members of the TGF-b signalling superfamily which signal through SMAD4 and are generally associated with an oncogenic process, with differing effects on tumour and stromal cells, such as cancer associated fibroblasts (CAFs). We sought to further elucidate the role of activin within PDAC and perturb activin signalling in vitro and in vivo. Analysis was performed of publicly available human datasets alongside human and murine single-cell RNA-sequencing datasets to study the effect of activin expression on survival and tumourigenesis. We developed anti-activin monoclonal antibodies to perturb activin signalling in PDAC mice, with deep analysis of tumour composition including immune cells and CAFs via a multitude of basic science techniques. We demonstrated that circulating activin levels are higher in PDAC patients than in healthy volunteers, whilst activin overexpression is associated with reduced overall survival in PDAC patients. Activin was shown to be predominantly expressed by contractile (collagen-depositing) CAFs, as opposed to inflammatory CAFs. Activin expression co-localises with fibroblasts, and anti-activin antibodies can reduce the collagen content of dense PDAC tumours. Additionally, anti-activin antibodies led to a statistically significant increase in CD4 and CD8 T-cell infiltration into murine PDAC tumours. We have shown that activin is overexpressed in PDAC, and high expression is associated with a more aggressive disease process. Anti-activin antibodies can alter the composition of desmoplastic PDAC tumours and increase the immune infiltrate of these typically “immune cold” tumours.