# The role of eosinophils and oxidative stress in esophageal malignancy

> **NIH VA IK2** · VETERANS HEALTH ADMINISTRATION · 2020 · —

## Abstract

The poor survival, high prevalence of smoking and alcohol use, and advanced stage at diagnosis of esophageal
squamous cell carcinoma (ESCC) in the VA population necessitates further study into new management
strategies for squamous cell carcinoma. Over the past few years, emerging immunotherapy approaches, such
as adoptive cell transfer, have highlighted the importance of understanding and manipulating the tumor
microenvironment. The tumor microenvironment in ESCC is understudied. In this proposal, we focus on
determining the role of eosinophils, a key component of the microenvironment, in ESCC. We have generated
preliminary data demonstrating the presence of eosinophils in human ESCC tumors but not in tumor-adjacent
tissue. We then established and characterized the 4-nitroquinolone-1-oxide (4-NQO) murine model of as a
feasible model for determining the function of eosinophils in the tumor microenvironment. We show that, in the
4-NQO model, eosinophils are constantly being produced by the bone marrow, recruited specifically to areas of
esophageal dysplasia as in human ESCC, and not present in areas without dysplasia. Additionally, Eotaxin-1
(CCL11), a potent eosinophil chemoattractant, is induced in areas of dysplasia. These observations suggest that
eosinophils play a tumor specific role and are not the result of a more general inflammatory response. While the
4-NQO model will be employed to generate a broader understanding of eosinophils’ role in tumorigenesis,
sophisticated co-culture techniques the we have developed provide mechanistic insights into eosinophil
activation and function in tumor biology. In this proposal we show that eosinophils co-cultured with esophageal
cells increases apoptosis, decreases viability, and alters the cytokine profile of epithelial cells, increasing
expression of TNF-a and IL-2, IL-8, and IL-10. Furthermore, eosinophils, which produce reactive oxygen species
(ROS), have increased expression of eosinophil peroxidase after co-culture with epithelial cells. This is significant
as eosinophil peroxidase is known to catalyze the oxidation of halides and thiocyanate, resulting in the release
of cytotoxic reactive oxidant species. Taken together, these data suggest that eosinophils may decrease viability
ESCC cells via release of ROS. Glutathione Peroxidase 1 (Gpx1), an abundant antioxidant enzyme expressed
by eosinophils, catalyzes the reduction of hydrogen peroxide or lipid peroxidases to water. Here we
independently propose that Gpx1 regulates ROS production by eosinophils, and the decrease in expression of
Gpx1 by eosinophils after co-culture with esophageal epithelial cells suggests it is modified by the eosinophil-
epithelial interaction. In light of these data and the recruitment of eosinophils specifically to areas of dysplasia
and carcinoma in ESCC, our overarching hypothesis is that eosinophils are cytotoxic to tumor cells and
thus are protective in ESCC. The specific aims for this project are: 1. To determine...

## Key facts

- **NIH application ID:** 9782560
- **Project number:** 1IK2BX004648-01
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** Yash Choksi
- **Activity code:** IK2 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2019-10-01 → 2024-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9782560

## Citation

> US National Institutes of Health, RePORTER application 9782560, The role of eosinophils and oxidative stress in esophageal malignancy (1IK2BX004648-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9782560. Licensed CC0.

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