# Promoting Activated Natural Killer (NK) Cell Accumulation in Pancreatic Cancer

> **NIH NIH F30** · GEORGETOWN UNIVERSITY · 2024 · $36,274

## Abstract

PROJECT SUMMARY/ABSTRACT
Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer, with a 5-year survival
rate of only 12%. Immunotherapy, such as anti-PD1 antibody (α-PD1) treatment, has been largely ineffective in
PDAC. Although T cells and natural killer (NK) cells both have potent anti-tumor effects, most immunotherapy
research has focused on modulating T-cell activity. Thus, the function of NK cells is highly understudied in PDAC.
Utilizing imaging mass cytometry (IMC), a novel multiplex imaging platform, our laboratory has made the
surprising and potentially important observation that activated NK cells, but not T cells, preferentially
co-localize with tumor epithelial cells in the PDAC tumor microenvironment (TME). This discovery warrants
investigating strategies and anti-tumor effects of increasing co-localization of activated NK and tumor cells. Here,
we demonstrate that pan-inhibition of dipeptidyl peptidases (DPPs), enzymes known to be involved in cancer
progression and blocking immune activation, using the pan-DPP inhibitor BXCL701 (701) enhances the efficacy
of α-PD1 therapy in syngeneic, murine PDAC models. This effect is associated with increased NK cell infiltration,
reduction in fibrosis, and increased expression of CXCL9, CXCL10, and IL-18. Notably, we found that individual
DPP inhibition demonstrates minimal anti-tumor effects as compared to pan-DPP inhibition. Furthermore, by
analyzing publicly available datasets and in vitro assays, we found that the NK cell-attractant chemokines CCL3
and CXCL11 are relatively underexpressed in PDAC. This suggests that creation of site-specific chemokine
gradients using CCL3/CXCL11 can serve to increase NK cell accumulation. Based on these observations, I
hypothesize that increasing co-localization of activated NK cells with tumor cells in PDAC will promote
anti-tumor effects. To test this hypothesis, I aim to determine the impact of DPP inhibition on the spatial and
functional status of NK cells in the murine PDAC TME utilizing IMC (Aim 1A), assess the therapeutic impact of
depleting CXCL9, CXCL10, and IL-18 on anti-tumor effects mediated by 701+α-PD1 therapy in vivo (Aim 1B),
and manipulate CCL3/CXCL11 expression in the PDAC TME to enhance NK cell migration in vitro (Aim 2A) and
anti-tumor responses in vivo (Aim 2B). Successful completion of these aims will identify factors that regulate NK
cell infiltration in the PDAC TME and the impact of NK cell-tumor epithelial cell co-localization on immune
responses. These findings will fill the gap in knowledge surrounding intra-tumoral NK cell migration, localization,
and functional status in PDAC and provide new approaches for exploiting NK cells to enhance anti-tumor immune
activity.

## Key facts

- **NIH application ID:** 10995994
- **Project number:** 1F30CA294875-01
- **Recipient organization:** GEORGETOWN UNIVERSITY
- **Principal Investigator:** Alexander Lekan
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $36,274
- **Award type:** 1
- **Project period:** 2024-09-01 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10995994

## Citation

> US National Institutes of Health, RePORTER application 10995994, Promoting Activated Natural Killer (NK) Cell Accumulation in Pancreatic Cancer (1F30CA294875-01). Retrieved via AI Analytics 2026-06-03 from https://api.ai-analytics.org/grant/nih/10995994. Licensed CC0.

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