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

> **NIH NIH F31** · GEORGETOWN UNIVERSITY · 2022 · $34,052

## Abstract

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.

## Key facts

- **NIH application ID:** 10386315
- **Project number:** 1F31CA261125-01A1
- **Recipient organization:** GEORGETOWN UNIVERSITY
- **Principal Investigator:** Zoe Xenos Malchiodi
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $34,052
- **Award type:** 1
- **Project period:** 2022-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10386315

## Citation

> US National Institutes of Health, RePORTER application 10386315, Pancreatic Stellate Cell (PSC) Engagement of Natural Killer (NK) cells in the Pancreatic Ductal Adenocarcinoma (PDAC) Tumor Microenvironment (1F31CA261125-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10386315. Licensed CC0.

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