Fibroblast activation protein (FAP) is a type II transmembrane serine protease that functions as both a dipeptidyl peptidase and an endopeptidase. FAP is minimally expressed in normal pancreas but overexpressed in 90% of pancreatic ductal adenocarcinoma (PDAC) specimens. A meta-analysis of PDAC studies demonstrated elevated tumor FAP expression is associated with worse clinical outcomes. While immunotherapy offers remarkable results for certain cancer types, it has been largely ineffective in PDAC. This lack of efficacy may be attributed to the dense stromal fibrosis, comprised largely of pancreatic stellate cells (PSCs), that is characteristic of PDAC lesions. Here we demonstrate that human NK cell line (NK92) is activated by and kill PSCs. Upon direct contact with PSCs, NK92 cells upregulate FAP. FAP expression by NK92 cells is associated with an inactivation phenotype. Talabostat, a non-specific inhibitor of FAP, enhances NK92 killing of PSCs in vitro and enhances PDAC tumor clearance in vivo. This suggests that FAP may be a novel NK cell immune checkpoint that can be pharmacologically modulated to enhance NK cell antitumor activity.

Citation Format: Allison O'Connell, Shangzi Wang, Louis M. Weiner. The potential role of fibroblast activation protein as a natural killer cell immune checkpoint [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A096.