# Neutrophil Extracellular Traps and the Intersection of the Immune and Biophysical Microenvironments

> **NIH NIH F31** · UNIVERSITY OF CHICAGO · 2023 · $47,694

## Abstract

Project Summary: While immunotherapy has revolutionized cancer treatment in recent years, major
challenges still remain. Metastatic cancer remains difficult to treat, resulting in 90% of cancer deaths, and
only 20-40% of patients respond to immunotherapy, with varying levels of response across cancers. In
solid tumors, lymphatic activation, or lymphangiogenesis, is associated with both metastasis and improved
response to immunotherapy, and more recently, neutrophil activation has also emerged as playing a key role in
both of these processes. An important mechanism by which neutrophils promote cancer progression is through
the formation of neutrophil extracellular traps (NETs). NETs are a mesh network of decondensed DNA
dotted with histones and granular proteins, and they are released by neutrophils in order to trap and kill
pathogens, or in response to tumor-secreted cytokines. Many of these proteins are proteases, which have
the potential to remodel the extracellular matrix (ECM). In this proposal, we will explore the novel
hypothesis that lymphatics and neutrophils collaborate in driving pro-metastatic programs in ways that alter the
extracellular matrix (ECM) and host immune response. We will use immunofluorescence staining and second
harmonic generation imaging of tumors, lungs, and lymph nodes from 4T1 and B16 murine models of cancer to
characterize the cross-talk between NETosis, lymphangiogenesis and ECM in cancer metastasis. We will also
use an inducible model of lymphangiogenesis that is specific to the lung in order to determine if the effect of
NETosis on metastasis is specific to the pre-metastatic niche or the tumor microenvironment. We will use
physiological artificial ECM and 3D perfusion models of the tumor-lymph node microenvironment with ex vivo
tissues to determine how the biophysical properties of the tumor microenvironment affect NETosis and T cell
cytotoxicity, and how NETosis affects tumor progression and response to immunotherapy. Results from this
work could help us better predict which patients are likely to respond to immunotherapy and lead to new
therapeutic strategies that make immunotherapy more effective in more patients. It will also increase our
understanding of how the biophysical properties of the microenvironment affect immune cell function in
general, which is likely an important factor in many disease processes.

## Key facts

- **NIH application ID:** 10668216
- **Project number:** 5F31CA257763-03
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Margo MacDonald
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $47,694
- **Award type:** 5
- **Project period:** 2021-07-11 → 2024-07-10

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10668216

## Citation

> US National Institutes of Health, RePORTER application 10668216, Neutrophil Extracellular Traps and the Intersection of the Immune and Biophysical Microenvironments (5F31CA257763-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10668216. Licensed CC0.

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