# Mechanisms underlying therapy failure of immune checkpoint inhibitors and Notch1 loss-mediated immunosuppression in head and neck cancers

> **NIH NIH F31** · UNIVERSITY OF COLORADO DENVER · 2020 · $32,919

## Abstract

Project Summary
Head and Neck Squamous Cell Carcinoma (HNSCC) is a very prevalent cancer, affecting approximately
630,000 people per year. While every cancer has unique characteristics, HNSCC is especially heterogenous
due to a variety of tissue origins and mutations. Inactivating mutations in Notch1 occur in 15-20% of HNSCC
cases, a marked difference from the prevalence of Notch1 amplifications in other cancers. While Notch1
mutations are especially aggressive and associated with poor prognosis, we have also seen that they are
associated with reduced expression of co-inhibitory receptors on immune cells. While co-inhibitory receptors
are associated with immune exhaustion, they are also a natural consequence of immune cell activation. The
reduced expression of inhibitory receptors in tumor-infiltrating lymphocytes is likely a sign of reduced immune
activation. We will investigate the effect of Notch1 loss on the immunosuppressive environment in HNSCC and
determine how this important signaling molecule might be impacting immunosurveillance. On the other side of
the tumor-immune interaction, the other important question remains how to best block immune inhibition. Anti-
PD-1 therapy has been a popular new treatment, but is only effective in 10-20% of cases. However, PD-1 is
not the only inhibitory receptor on immune cells, and others such as lymphocyte activation gene-3 (LAG-3) are
equally important. We will investigate how dual inhibition of these receptors can be optimized with respect to
timing and strategic targeting of different receptors. The findings of these studies are expected to develop new
approaches to cancer immunotherapy and optimizing strategies to existing immunotherapy treatments.

## Key facts

- **NIH application ID:** 9848525
- **Project number:** 5F31DE027854-03
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Rachel A Woolaver
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $32,919
- **Award type:** 5
- **Project period:** 2018-02-01 → 2020-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9848525

## Citation

> US National Institutes of Health, RePORTER application 9848525, Mechanisms underlying therapy failure of immune checkpoint inhibitors and Notch1 loss-mediated immunosuppression in head and neck cancers (5F31DE027854-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9848525. Licensed CC0.

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