# The Impact of Metastatic Site On Dendritic Cell-Driven Tumor Immunity

> **NIH NIH U01** · WASHINGTON UNIVERSITY · 2024 · $612,272

## Abstract

Project Summary/Abstract
The prognosis for pancreatic ductal adenocarcinomas (PDAC) patients is dismal. Unfortunately, attempts at
immunotherapy for PDAC to date using single agents have not achieved significant clinical benefits. This is likely
due to the presence of a uniquely suppressive tumor microenvironment (TME). Our recent data suggest that
immune priming by dendritic cells (cDCs) may ultimately a rate-liming barrier to productive anti-tumor immunity.
While the focus of research in pancreatic cancer has been on the TME during primary disease, we are only
now realizing how significant the differences in the TME are between primary and metastatic disease and/or
metastatic lesions in different organs. These differences are critical, as the majority of immunotherapeutic
approaches are being tested in refractory metastatic PDAC patients. We will address this shortcoming in
understanding metastatic PDAC biology by determining the differential impact of metastatic disease site(s) on
immune priming by cDCs. cDCs are central for generating tumor antigen-specific T-cell responses. In animal
models and human correlative studies, cDCs are crucial for responsiveness to both cytotoxic and checkpoint
immunotherapies. Our published data show that cDCs were severely dysfunctional in PDAC patients and that
this dysfunction was driven by two distinct mechanisms. First, we reported that PDAC patients had impaired cDC
development in their bone marrow, which led to a functional depletion of circulating pre-DCs, impaired cross-presentation
of tumor antigens, and poor responses to checkpoint inhibitors. Even when DC development is not
fully impaired, we've shown cDCs are dysfunctional and excluded from the PDAC TME. Overall, these
mechanisms impair the ability of conventional therapies to prime tumor antigen-specific T-cell responses and
checkpoint immunotherapy to drive efficacy. Together these data support our hypothesis that metastatic organ
site-specific drivers lead to divergent effects on local and systemic tumor immunities. We will directly
address this hypothesis with the following aims:
Aim 1. Determine the impacts of the site of metastatic disease on immune priming by cDCs.
Aim 2. Determine the impacts of the site of metastatic disease on systemic immunity and cDC
development.
Aim 3. Determine how therapy differentially shapes the TME at different metastatic sites to impact
immune priming.
Significance: These understandings are critical for the treatment of mPDAC patients.

## Key facts

- **NIH application ID:** 10931531
- **Project number:** 5U01CA284086-02
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** David G DeNardo
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $612,272
- **Award type:** 5
- **Project period:** 2023-09-19 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10931531

## Citation

> US National Institutes of Health, RePORTER application 10931531, The Impact of Metastatic Site On Dendritic Cell-Driven Tumor Immunity (5U01CA284086-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10931531. Licensed CC0.

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