Pancreatic Stellate Cell (PSC) Engagement of Natural Killer (NK) cells in the Pancreatic Ductal Adenocarcinoma (PDAC) Tumor Microenvironment

Abstract public domain (NIH RePORTER)

PROJECT SUMMARY/ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer, with a 5-year survival rate of less than 10%. One of the hallmarks of PDAC is immune suppression, which is mediated in part by a heterogenous cancer-associated fibroblast (CAF) population, also termed pancreatic stellate cells (PSCs). PSCs can exist as both tumor-promoting and tumor-restrictive subpopulations. Our laboratory recently showed that human natural killer (NK) cells interact with and lyse activated PSCs via a NKG2D-MICA/B NK cell receptor- ligand interaction. NK cells are cytotoxic components of the innate immune system; their functions are highly understudied in PDAC. Our laboratory also had made the novel and potentially important observations that activated, cytotoxic, NK cells are relatively abundant in the PDAC tumor microenvironment (TME), and that high expression of NK cell markers correlates with better PDAC patient survival. Based on these observations, I hypothesize that one important role of PSCs is to divert NK cells from malignant epithelial PDAC cells in the tumor microenvironment (TME), protecting tumors from immune attack. Therefore, this project’s first aim is to explore the interactions between fibroblast activation protein (FAP)+ PSCs with NK cells in PDAC. NK cell receptor-ligand interactions that regulate NK cell-mediated lysis of FAP+ PSCs will be further studied in vitro. The spatial relationships between NK cells and FAP+ PSCs will also be defined using a human PDAC tumor microarray by Imaging Mass Cytometry. The second aim is to examine the impact of NK cells and FAP+ PSCs on tumor growth. In a murine PDAC model, FAP+ PSCs will be depleted using a FAP-specific catalytic immunotoxin to assess the impact of FAP+ PSC depletion on PDAC and NK cell invasion, phenotype, and function. NK cells will also be selectively depleted in a murine PDAC model in order to determine their impact on tumor growth, FAP+ PSC phenotype and function in the PDAC TME. This work will employ single-cell RNA sequencing analysis to assess transcriptional changes in the PDAC TME as a function of these depletion studies. Combinations of NK cell enhancement/activation with FAP+ PSC depletion will define the potential translational relevance for future therapy strategies. Successful completion of these aims will elucidate the relevance of NK cell-PSC interactions in PDAC and will lay the groundwork for exploiting the innate immune system to increase the efficacy of the anti-tumor immune response.

Public health relevance public domain (NIH RePORTER)

PROJECT NARRATIVE Tumor-promoting pancreatic stellate cells (PSCs) may suppress the ability of natural killer (NK) cells to attack malignant pancreatic ductal adenocarcinoma (PDAC) cells, therefore I aim to examine the molecular mechanisms that regulate the interactions of NK cells with fibroblast activation protein (FAP)+ expressing PSCs. I also will deplete FAP+ PSCs to determine if this unleashes NK cell mediated tumor lysis in vivo. Successful execution of this project will provide a novel therapeutic strategy to effectively treat PDAC.