# Research Project  Pancreatic Cancer

> **NIH NIH U54** · WASHINGTON UNIVERSITY · 2024 · $258,389

## Abstract

PROJECT 2 (PANCREAS) SUMMARY
The prognosis for pancreatic ductal adenocarcinomas (PDAC) patients is dismal. Unfortunately, attempts at
immunotherapy for PDAC to date have not achieved significant clinical benefits. It is widely accepted that
radiation therapy (RT) can prime anti-tumor immunity by releasing tumor-derived antigens and danger signals,
and this immune priming effect has a crucial role in RT efficacy in multiple cancer types. In contrast, combining
RT with checkpoint immunotherapy has been generally underwhelming in PDAC. It is unclear if this reflects an
inability of RT to prime tumor-specific T cells or a need for additional stimulants that are supportive of T-cell
priming. Dendritic cells (cDCs) are central for generating tumor antigen-specific T-cell responses. In animal
models and human correlative studies, cDCs are crucial for responsiveness to checkpoint immunotherapy and
RT-induced tumor immunity. Our hypothesis is that RT drives divergent effects on local and systemic tumor
immunities through regulation of cDCs. We will directly address this hypothesis, focusing on how DCs and
T-cell responses are co-shaped during SOC RT. We will use a combination of scRNAseq, spatially resolved
protein, metabolomic profiling in human PDAC tissues and mouse models to test the following. In Aim 1, we will
determine the local and systemic impacts of RT on local immune priming by cDCs. These studies will use a
combination of longitudinally collected human tissues from patients undergoing SBRT and genetically
engineered mouse models (GEMMs) to assess the impact of RT on DC phenotype and function. Leveraging our
institutional strengths, we will conduct these studies in three cohorts of prospective and retrospective tissue
collections from human PDAC patients receiving SBRT and conduct mechanistic studies using PDAC GEMMs.
These studies will assess the local impact of SBRT on cDC function. In Aim 2, we will determine the impact of
RT on cDC differentiation and systemic immunity in PDAC patients. Our data in both human PDAC patients and
mouse models demonstrated that key differences in myelopoiesis and cDC development in PDAC can impair
tumor immunity. Furthermore, our preliminary data indicated that SBRT could alter cDC development and
phenotype. In this aim, we will use a combination of human tissues and GEMMs to specifically study how RTs
impact systemic DC development, phenotype and function, and the net impact this has on tumor immunity and
T-cell priming in response to RT. In Aim 3, we will determine the impact of RT on interactions between regional
metabolism and cDC-directed T-cell immunity. RT can have a dramatic impact on tumor and stromal cell
metabolism. In parallel, these metabolic changes can regulate cDC and T-cell survival and function. However,
these interactions have not been well studied in the context of intact PDAC tissues, where regional heterogeneity
in immune infiltrate, hypoxia, and stromal density are dominant players. We w...

## Key facts

- **NIH application ID:** 10912704
- **Project number:** 5U54CA274318-02
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** David G DeNardo
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $258,389
- **Award type:** 5
- **Project period:** 2023-09-01 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10912704

## Citation

> US National Institutes of Health, RePORTER application 10912704, Research Project  Pancreatic Cancer (5U54CA274318-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10912704. Licensed CC0.

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