# An Environmental Chemical Receptor, the AhR, as a Mediator of Multiple Immune Checkpoints in Oral Cancer

> **NIH NIH R01** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2024 · $457,675

## Abstract

The prognosis for patients with HNSCC is grim with only 40%-50% of patients surviving 5 years. Surgery,
radiation and chemotherapy are debilitating with high morbidity. Immunotherapy has shown some dramatic
results. However, complete responses are rare and only a minority of HNSCC patients benefit. Therefore,
there is an unmet need to understand factors controlling HNSCC-specific immunity and to plot out novel
strategies for improved targeting. This project addresses these two goals. Accumulating evidence indicates
that the AhR, an environmental chemical receptor, is highly expressed and chronically active in many cancers
including HNSCC even in the absence of xenobiotics and regardless of tumor etiology. Chronic AhR activity
can be initiated by environmental chemicals but maintained through an AhRIDO kynurenine pathway
(endogenous AhR agonist) amplification loop. In a mouse oral cancer (MOC1) model, short-circuiting this loop
by deleting the AhR from malignant cells decreases immunosuppressive IDO1 and PD-L1 and, following
orthotopic transplant, renders mice completely immune to challenge with wildtype tumor. MOC1AhR-KO cell-
induced immunity is accompanied by a spike in CD4+ and CD8+ T cells and a diminution of: 1) PD1+, Lag3+,
CTLA4+, and CD39+ T cells, 2) PD-L1+ and CD39+ granulocytes (G-MDSCs), 3) PD-L1+ dendritic cells (DC),
and 4) CD39+ and CCR2+ macrophages (MΦs), all of which contribute to poor HNSCC outcomes. We
postulate that the AhR circuit in MOC cells upregulates PD-L1 and, via endogenous ligand production, skews
AhR+ MΦs, G-MDSCs, and/or DCs in the TME towards immunosuppression. Thus, our central hypothesis is
that the AhR mediates multiple immune checkpoints in HNSCC and thereby represents an attractive
immunotherapy target. Three specific aims are proposed: Map the effects of AhR, IDO and PD-L1 knockout
in malignant cells on the spatial location and interactions of immune cells in tdLNs and the TME.
CRISPR/Cas9 gene editing will determine the relative contributions of AhR-regulated PD-L1 and IDO in
immunosuppression (1.1) and Imaging Mass Cytometry will define the spatial relationship of AhR+ immune
subsets and AhR+ MOC1 cells in the TME (1.2). Aim 2: Define the immunosuppressive role of the AhR in
host immune cell subsets. Conditional AhR knockout mice will be used to determine the requirement for AhR
expression in G-MDSCs, MΦs, and DCs in HNSCC-induced immunosuppression (2.1) and scRNA-seq data
will define immune subset representation (2.2). Aim 3: Determine mechanisms of action of AhR inhibitors
in HNSCC preclinical models. The cellular targets of an AhR inhibitor will be determined and compared with
immune profiles seen after MOC1AhR-KO cell transplant (3.1); the effects of AhR inhibitor specifically on host
cells will be defined (3.2), and the effects of AhR knockout in MOC1 cells and AhR inhibitor on tumor antigen-
specific T cells compared (3.3). This collaborative project, with its use of innovative approaches, has the
...

## Key facts

- **NIH application ID:** 10876935
- **Project number:** 5R01ES033692-03
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** David H Sherr
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $457,675
- **Award type:** 5
- **Project period:** 2022-09-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10876935

## Citation

> US National Institutes of Health, RePORTER application 10876935, An Environmental Chemical Receptor, the AhR, as a Mediator of Multiple Immune Checkpoints in Oral Cancer (5R01ES033692-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10876935. Licensed CC0.

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