# Microenvironment and Arsenic Lung Tumorigenesis

> **NIH NIH R01** · UNIVERSITY OF KENTUCKY · 2020 · $344,250

## Abstract

Abstract
 Chronic exposure of environmental arsenic promotes skin, bladder, liver and lung cancers. However,
the mechanism underlying arsenic lung carcinogenesis is unclear. Evidence from animal models and studies in
cancer patients indicate that the immune system monitors the host body recognizing and reacting against
newly arising transformed/tumor cells to stop/control tumor formation. The encounter between the immune
system and transformed/tumor cells initiates a process termed “immunoediting” that can bring about three
outcomes: elimination, equilibrium or escape of transformed/tumor cells from immune control. Host immunity
suppresses tumor development, whereas tumor formation implies the successful escape of transformed/tumor
cells from the surveillance of the immune system. Effector T cells, particularly cytotoxic T (Tc) cells, represent
a major component of cell-mediated anti-tumor immunity. One of the mechanisms modulating T cell antitumor
effector function involves the activation/inhibition receptors on a T cell membrane. Inhibition of T cell antitumor
function through the activation of immune checkpoint pathways (e.g. PD-1/PD-L1 pathway) has been shown to
promote tumor cell immune escape and tumor formation. In addition, previous reports indicate that the aberrant
activation of STAT3 occurs in many human tumors and STAT3-mediated PD-L1 up-regulation impedes T cell
antitumor function. Our previous in vitro study showed that the IL-6/STAT3 axis plays a critical role in arsenic-
induced transformation in human bronchial epithelial cells. Using a lung tumor mouse model, our new
preliminary data show that long-term arsenic exposure increased lung tumor incidence rate and multiplicity of
A/J mice. In addition, arsenic exposure dose-dependently activated STAT3, increased the binding of STAT3 to
the promoter of the PD-L1 gene and up-regulated PD-L1 in mouse lungs. Flow cytometry data further indicated
that arsenic increased PD-1+ T cell numbers and decreased CD8+/CD4+ T cell ratio in the lungs, while injection
of PD-1 or PD-L1 antibodies reversed the decreased CD8+/CD4+ ratio. Since PD-1/PD-L1 up-regulation may
inhibit T cell antitumor function and promote escape of transformed cells from host immunosurveillance and
eventually lead to tumor formation, we hypothesize that arsenic promotes lung tumor formation through
STAT3/PD-1/PD-L1-mediated inhibition of T cell antitumor function. Three specific aims are proposed:
Aim 1: To determine if chronic arsenic exposure inhibits T cell antitumor function and the types of cells in
which PD-1 or PD-L1 is up-regulated by arsenic in the lungs of A/J mice.
Aim 2: To determine if inhibition of the PD-1/PD-L1 pathway ameliorates arsenic-promoted T cell dysfunction
and tumor formation in the lungs of A/J mice.
Aim 3: To determine if activation of STAT3 is the mechanism underlying arsenic-enhanced PD-L1 up-
regulation, T cell dysfunction and tumor formation in the lungs of A/J mice.

## Key facts

- **NIH application ID:** 9989613
- **Project number:** 5R01ES026657-04
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** Gang Chen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $344,250
- **Award type:** 5
- **Project period:** 2017-09-30 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9989613

## Citation

> US National Institutes of Health, RePORTER application 9989613, Microenvironment and Arsenic Lung Tumorigenesis (5R01ES026657-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9989613. Licensed CC0.

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