# Robust Immuno-prevention Strategies for High-Risk Oral Epithelial Dysplasia

> **NIH NIH U01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $158,870

## Abstract

PROJECT SUMMARY
 Immune checkpoint blockade has proven an effective treatment for a subset of head and neck cancer
(HNC) patients. However, over 85% of the patients cannot benefit from this strategy, largely due to the highly
immunosuppressive tumor microenvironment (TME) in established cancers. Oral leukoplakias / Oral Epithelial
Dysplasias (OEDs) precede HNC and offer a unique time window for disease eradication. However, surgical
resection in the orofacial region results in significant morbidity and function loss, and more importantly, cannot
reverse field cancerization. A subset of OEDs transform into malignancy despite vigilant follow-ups. Frequent
immune cell infiltration is a common feature of OEDs, however, little is known about when and how OEDs
evade from immuno-surveillance and reach a point-of-no-return. In addition, it remains unclear which sub-
group of OEDs is more likely to suppress host immunity and establish themselves as high-risk lesions.
Amplification of the chromosome locus 3q26.3 is a defining genomic feature of HNC, and two oncogenes at
this locus inhibit innate immune sensing pathways and elicit a metabolic restraint in the TME, which collectively
disadvantage anti-tumor immune cells. We have developed strategies to bypass the inhibition of innate
immune sensing and synthesized a novel drug-like molecule that exhibits potent metabolic remodeling
potential and anti-tumor activity in vivo. We constructed two unique genetically engineered mouse models,
which can model a spectrum of OED/HNC lesions with high-fidelity histologic and immunophenotypic
resemblance to human diseases, to recapitulate 3q26.3-driven OED transformation. We also identified unique
collections of case-control and longitudinal paired OED/HNC specimens, which allow us to validate key
findings on the temporal shift of exploitable immune targets with clinical specimens. The overarching goal of
this translational program is to test the hypothesis that 3q26.3 amplification is a key early high-risk event that
leads to OED immune escape and that a combination of metabolic remodeling agent with immunotherapy
effectively prevents OED progression. Thus, this proposal is fully responsive to the RFA-CA-19-014 and is
focused on the deeper understanding of the time-course of immune landscape shift as pre-malignant lesions
progress, using 3q26.3 amplification-driven OEDs as a high-risk disease model. We will qualify a novel
metabolic remodeling drug-like molecule as a priming agent to maximally improve immuno-prevention. The
3q26.3 amplification is not unique to HNC and commonly found in squamous cell carcinomas of the lung,
esophagus and skin, hence, our findings will help address a broad class of public health concerns.

## Key facts

- **NIH application ID:** 10384385
- **Project number:** 3U01DE029255-01S1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** John Chadwick Brenner
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $158,870
- **Award type:** 3
- **Project period:** 2021-04-06 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10384385

## Citation

> US National Institutes of Health, RePORTER application 10384385, Robust Immuno-prevention Strategies for High-Risk Oral Epithelial Dysplasia (3U01DE029255-01S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10384385. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*