Pancreatic Cancer Precursor Lesions – Can Immunotherapy Prevent Progression into Pancreatic Ductal Adenocarcinoma?

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, with a 5-year survival rate of only 12.5%. Early detection of PDAC or addressing risk factors for PDAC development are ways to improve outcomes. PDAC can arise from precursor lesions, including pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasm (IPMN), and less frequent, mucinous cystic neoplasm (MCN), and other rare precursor variants. High-risk precursor lesions harbor a substantial chance of evolving into PDAC. Such lesions can often be found in resected PDAC specimens adjacent to the cancer. Unfortunately, recognizing precursor lesions that need to be resected is often tricky, and resections frequently end in major surgical interventions. Thus, better ways to handle precursor lesions are desperately needed. We mapped the immune microenvironments (IMEs) of PanINs, IPMNs, and MCNs on a cellular level using multiplex immunofluorescence and computational imaging technology and compared the findings to PDACs and normal pancreatic tissues. We found distinct and potentially targetable mechanisms of immunosuppression between the two main precursor lesions, PanIN and IMPN. Immunosuppression in IPMNs seems partly mediated by programmed cell death protein 1 ligand (PD-L1) expression on antigen-presenting cells (APCs). By contrast, elevated numbers of regulatory T cells (Tregs) seem to be key players in the immunosuppression of PanINs. Thus, treating high-risk IPMNs with anti-PD-1 and high-risk PanINs with agents targeting Tregs, such as anti-lymphocyte associated protein 4 (anti-CTLA-4) antibodies, could reverse their immunosuppressive state. Reversal of immunosuppression will restore immunosurveillance and eventually prevent progression into PDAC. We also review relevant published and ongoing non-surgical treatment approaches for high-risk IPMNs and PanINs.