# The Induction of Macrophage Endoplasmic Reticulum Stress by Irradiated-Tumor Derived Extracellular Vesicles Supports the Adoption of a Pro-Tumor Phenotype

> **NIH NIH F30** · VIRGINIA COMMONWEALTH UNIVERSITY · 2020 · $38,181

## Abstract

Project Summary
Radiotherapy initiates the recruitment of alternatively stimulated (M2) macrophages to the tumor
microenvironment. These cells exhibit a “pro-tumor phenotype,” stimulating angiogenesis, suppressing anti-
tumor immunity, and enhancing tumor cell radioresistence. This limits the overall efficacy of radiotherapy for
solid tumors such as non-small cell lung cancer. Current research in the field of radioimmunology is focused on
manipulations that either inhibit the recruitment of these cells or that alter their behavior once they reach the
tumor microenvironment. However, exactly how irradiated cancer cells manipulate macrophages is largely
unknown. We have discovered that extracellular vesicles elaborated by irradiated lung cancer cells (IR-EVs)
induce ER-stress and elicit the production of “pro-tumor” cytokines from macrophages in an SRA/CD204
dependent manner. The overall objective of this project is to define the molecular mechanisms by which IR-EVs
induce macrophage pro-tumor cytokine expression. First, we will test the functional impact of IR-EV induced
macrophage ER stress on macrophage phenotype using CHOP-/- C57BL/6 mice and soluble inhibitors of ER
stress. Then, we will investigate the role of macrophage SRA/CD204 in the response of macrophages to IR-EVs.
We will do this using SRA/CD204-/- C57BL/6 mice as well as a novel SRA/CD204 blocking antibody developed
in our laboratory. Finally, we will compare the circulating IR-EVs of recurrent and non-recurrent non-small cell
lung cancer patients to determine if they can predict the outcome of radiotherapy. EVs from recurrent and non-
recurrent NSCLC patients isolated before, during, and after RT will be assessed for their ability to stimulate a
pro-tumor macrophage phenotype in vitro. Then, mass spectrometry will be used to identify a potential
SRA/CD204 binding protein upregulated on the surface of IR-EVs from patients and cultured cells. The potential
of ligand bearing exosomes to segregate lung cancer patients into relapse or disease-free survival groups will
be evaluated using a commercially available ELISA on concentrated serum exosomes.

## Key facts

- **NIH application ID:** 9930432
- **Project number:** 5F30CA239564-02
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** Gene Chatman Clark
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $38,181
- **Award type:** 5
- **Project period:** 2019-05-15 → 2024-05-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9930432

## Citation

> US National Institutes of Health, RePORTER application 9930432, The Induction of Macrophage Endoplasmic Reticulum Stress by Irradiated-Tumor Derived Extracellular Vesicles Supports the Adoption of a Pro-Tumor Phenotype (5F30CA239564-02). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9930432. Licensed CC0.

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