# Regulation and role of fibroblast-derived interleukin-33 in the pancreatic tumor microenvironment

> **NIH NIH F31** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $46,752

## Abstract

PROJECT SUMMARY/ABSTRACT
Pancreatic ductal adenocarcinoma (PDA) is a highly deadly disease with a five-year survival rate of only 10%.
The bulk of the PDA tumor volume is composed of a reactive fibroinflammatory tumor microenvironment that
assists in the growth and maintenance of the tumor. The highly immunosuppressive nature of the pancreatic
tumor microenvironment is also responsible, in part, for the continued inefficacy of immunotherapy treatments
in PDA patients. Despite numerous studies that have previously examined different facets of PDA
immunosuppression, there is still much that is unknown regarding the complex network of intercellular
crosstalk that regulates this phenomenon. Our previous work has demonstrated that infiltrating macrophages
are essential mediators of immunosuppression in PDA, and that their polarization is affected by the expression
of oncogenic Kras in tumor cells. Other groups have characterized the immunosuppressive impact of certain
fibroblast subgroups within the pancreatic tumor microenvironment. Preliminary experiments described in this
proposal demonstrate a connection between fibroblasts, macrophages, and tumor cells through fibroblast
expression of the cytokine interleukin-33 (IL33). The role of IL33 in cancer biology is controversial, with its
overall effect on the tumor thought to be supportive or suppressive depending on the cancer context. Here,
results show that IL33 abundance correlates with disease progression and that fibroblast expression of IL33 is
dependent on oncogenic Kras-driven signals from tumor cells. Additionally, we have completed a pilot
experiment whereby we have orthotopically implanted pancreatic tumor cells into a syngeneic genetically
engineered mouse model lacking Il33 in fibroblasts (Il33f/f, Pdgfra-CreERT2/+). Tumors from Il33-deficient mice
had slower tumor growth and a trending decrease in macrophage infiltration, suggesting that fibroblast-derived
Il33 is both tumor promoting and may play a role in the recruitment of immunosuppressive macrophages.
Therefore, the overall objective of this study is to elucidate the cellular interactions that contribute to the
establishment and maintenance of immunosuppression in PDA, and the central hypothesis is that fibroblast
derived IL33 is a key regulator of immunosuppression in the pancreatic tumor microenvironment through its
modulation of macrophage infiltration. This hypothesis will be investigated through the following two Aims:
(Aim 1) define the regulation and role of IL33 in cancer-associated fibroblasts, and (Aim 2) assess the impact
of IL33 on the recruitment of tumor-associated macrophages. To complete this investigation, a combination of
in vitro assays using tumor cell, fibroblast, and macrophage cultures will be performed. We also will continue to
utilize the Il33f/f, Pdgfra-CreERT2/+ genetically engineered mouse model to assess Il33-dependent changes in
the immunosuppressive nature of pancreatic tumors. The data accumulated by t...

## Key facts

- **NIH application ID:** 10461248
- **Project number:** 1F31CA265085-01A1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Katelyn Lois Donahue
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $46,752
- **Award type:** 1
- **Project period:** 2022-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10461248

## Citation

> US National Institutes of Health, RePORTER application 10461248, Regulation and role of fibroblast-derived interleukin-33 in the pancreatic tumor microenvironment (1F31CA265085-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10461248. Licensed CC0.

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