# Role of environmental toxins in shaping the tumor immune microenvironment

> **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2022 · —

## Abstract

ABSTRACT
 Pancreas adenocarcinoma (PDAC) is the third leading cause of cancer related deaths in the United States
and remains among the most lethal cancers with an expected 5-year survival of <10%. Environmental
exposures to chemicals such as those found in cigarette smoke, Agent Orange (dioxin; TCDD) and diet may
underlie a continued rise in PDAC incidence in veterans through unknown mechanisms. Strong evidence
implicates chronic inflammation as the link between exposure to toxins and PDAC tumorigenesis though the
exact mediators remain unknown. Interleukin-22 (IL22) has emerged as an important cytokine in host defense
and tissue repair in the pancreas. Although generally protective, chronically elevated levels have been
implicated in development of dysplasia and cancer. A defining feature of IL22-producing cells is their reliance
on the toxin binding, aryl hydrocarbon receptor (AhR), thought to represent an “environmental sensor” of the
immune system, and recently implicated in increased pancreatic IL22 signaling. We recently discovered that
AhR ligands promote IL22 production which can induce early malignant transformation of pancreatic epithelial
cells through enhancement of ERK signaling positioning IL22 as the possible missing link in toxin mediated
carcinogenesis. Important questions remain unanswered including the critical immune components in IL22
secretion in physiologic and pathologic states. Also unknown is the target of cytokine signaling with previous
reports of activity in both fibroblasts and epithelial cells. Little is known about reliance of tumors on sustained
IL22 signaling for persistence and growth, a factor that has important therapeutic implications. In this research
proposal, we will use reporter mice to identify the cellular sources of IL22 in both the normal and cancerous
pancreas and define the role of AhR ligands in activating these cells. We will also investigate the principle
target of IL22 signaling in the pancreas as this could provide greater insights into the AhR/IL22 axis during
tumor development. Finally, we will determine if AhR blockade could serve as a clinically useful method of
disrupting toxin mediated tumorigenesis. Successful completion of this proposal will uncover an important link
between environmental exposures, inflammation and cancer formation and identify a novel mechanism by
which tissues interface with toxins in the microenvironment. Development of a strategy to decrease a factor
previously identified as a causative agent in chronic pancreatitis and cancer formation will have direct
translatability to veterans with PDAC as well as other exposure-related malignancies.

## Key facts

- **NIH application ID:** 10366833
- **Project number:** 1I01BX005777-01
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** Timothy Louis Frankel
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2022-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10366833

## Citation

> US National Institutes of Health, RePORTER application 10366833, Role of environmental toxins in shaping the tumor immune microenvironment (1I01BX005777-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10366833. Licensed CC0.

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