# Overcoming Immunotherapy Resistance Through Opioid Antagonism in Head and Neck Cancer

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $581,147

## Abstract

PROJECT SUMMARY
Current treatment for head and neck squamous cell carcinoma (HNSCC) results in 5-year survival rates
around 63%; however, treatment is often associated with significant pain as well as a 50% recurrence rate
within the first 2 years. Opioids are the primary strategy for pain control, and the drug requirement is high, with
dosages increasing as tolerance develops. The majority of HNSCC patients are prescribed opioids with
treatment; persisent opioid use continues during survivorship and in recurrent/metastatic (R/M) HNSCC
patients. While providing some pain relief, opioids can be immunosuppressive, which can impede treatment
response. Immune checkpoint inhibitors (ICIs) are the current first-line systemic treatment strategy for R/M
HNSCC patients, but fewer than 20% of patients respond to therapy. The impact of concomitant use of opioids
and ICI is currently unknown. Preliminary data using a study cohort of 66 R/M HNSCC patients who received
anti-PD1 monoclonal antibody therapy found that 63% of patients were actively taking opioids for pain prior to
treatment. In this cohort, high opioid usage was associated with lower intratumoral CD8+ T cell density in the
tumor biopsy tissue prior to treatment and significantly lower overall survival in response to ICI treatment.
Additionally, using a syngeneic orthotopic transplant mouse model, the Oprm1 gene was upregulated in tumor
infiltrating lymphocytes (TIL), and acute morphine administration reduced the CD8+ TIL frequency by 90% in
vivo. Methylnaltrexone (MNTX), a peripheral-acting OPRM1 antagonist, completely blocked the morphine-
induced immunosuppression in our mouse model. The hypothesis of this proposal is that exogenous opioids
given for analgesia suppress anti-tumor immunity via immune-mediated OPRM1 signaling. To test this
hypothesis, we will use preclinical mouse models to investigate the functional impact of OPRM1 signaling in
CD8+ T cells on anti-tumor immunity and tumor growth as well as determine the neoadjuvant potential of
MNTX to block opioid-induced immunosuppression and improve ICI response. Additionally, we will use single
cell RNA sequencing and multispectral imaging on preclinical and human tumor tissue to provide a single-cell
level view of anti-tumor immunity with direct consideration of the immunosuppressive effects of opioid usage.
We believe this proposal will lead to new strategies to overcome immunotherapy resistance, a critical need for
improving outcomes in HNSCC disease.

## Key facts

- **NIH application ID:** 10977814
- **Project number:** 1R01DE033473-01A1
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Nicole N Scheff
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $581,147
- **Award type:** 1
- **Project period:** 2024-07-01 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10977814

## Citation

> US National Institutes of Health, RePORTER application 10977814, Overcoming Immunotherapy Resistance Through Opioid Antagonism in Head and Neck Cancer (1R01DE033473-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10977814. Licensed CC0.

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