# Activation of immunosupressive oxidative stress response pathways by tobacco exposure in head and neck cancer

> **NIH VA I01** · MICHAEL E DEBAKEY VA MEDICAL CENTER · 2024 · —

## Abstract

In head and neck cancer (HNC) and many other solid tumor types immune checkpoint inhibitors (ICIs)
approaches are effective in just a subset of patients (e.g. 15-20%). Our in-depth analysis of multiple smoking-
related malignancies has revealed that tumor derived factors, both genetic and metabolic, may be far more
important in dictating a permissive tumor immune microenviroment (TIME) than previously appreciated. As
we continue to move forward with a plethora of new clinical trials trying different regimens of ICIs layered
upon standard of care chemotherapy and/or radiation we may very well be missing the mark by not
considering more strongly the genomic background and individual cancer biology underpinning the very
tumors being treated. We believe the next revolution in immune-oncology is more likely to stem from
combination therapy that directly targets the hidden biology of tumors that makes them dodge the immune
system rather than discovery of yet another ICI molecule. Specifically, we have accumulated a large body of
evidence that points to Nrf2 pathway activation as a major driver of cancer biology and immune escape. This
pathway in the context of immune checkpoints holds great theranostic promise for improving ICI outcomes
and at the same time for overcoming resistance to orthogonal standard of care chemotherapy and radiation.
 Here we will link tobacco exposure and Nrf2 across the biological spectrum of HNC by measuring the
temporal kinetics of tobacco exposure effects on Nrf2 activation in HNC (Subaim 1.1). Using a layered
approach we will measure the level of Nrf2 activation following chronic tobacco exposure and identify
downstream drivers of survival to oxidative stress generated by tobacco exposure in selected cell lines
(Subaim 1.2). Using established immunodeficient murine models of HNC we will then link tobacco exposure
to Nrf2 activation in vivo (Subaim 1.3) and demonstrate that pharmacologic inhibition of Nrf2 can reduce
tobacco exposure effects on downstream gene activation. In Aim 2 we will define the mechanisms by which
Nrf2 activation regulates TIME. We previously identified one key Nrf2 target, Gpx2 as a driver of a suppressive
TIME using human data and murine models of HNC. We will measure immune effects of acute and chronic
tobacco exposure as a function of Nrf2 activation and Gpx2 activity (Subaim 2.1) in vitro and using
immunocompetent HNC murine models as it relates to functional immunocytes (CD8+ T cells) and suppressor
MDSCs (Subaim 2.2). Finally, we will define the impact of tobacco induced Nrf2 activation on immune
checkpoint inhibitor (ICI) effectiveness in HNC. We will measure the impact of chronic smoke induced Nrf2
activation on ICI effectiveness in immunocompetent HNC models (Subaim 3.1) and test whether either direct
reversal of Nrf2 activity (ML385) or indirect inhibition of downstream effects via the glutaminase-1 (GLS1)
inhibitor IACS6274 can restore maximal ICI effectiveness in against HNC tumors (Subaim...

## Key facts

- **NIH application ID:** 10797603
- **Project number:** 1I01BX006380-01
- **Recipient organization:** MICHAEL E DEBAKEY VA MEDICAL CENTER
- **Principal Investigator:** VLAD C SANDULACHE
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2024-04-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10797603

## Citation

> US National Institutes of Health, RePORTER application 10797603, Activation of immunosupressive oxidative stress response pathways by tobacco exposure in head and neck cancer (1I01BX006380-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10797603. Licensed CC0.

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