# Targeting the innate immune response in HNSCC

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2023 · $498,386

## Abstract

Immune therapy holds great promise to improve disease outcomes for head and neck squamous cell carcinoma
(HNSCC) patients. The sixth most common cancer worldwide, HNSCC is a deadly and disfiguring disease that
accounted for more than 54,000 cases and 10,850 deaths in 2021 in the United States alone. Cases continue
to rise, in part due to increases in human papillomavirus (HPV) associated oropharynx cancers. The current
standard therapeutic regimens of surgery, chemotherapy and radiation therapy are associated with significant
morbidity and loss of quality of life with only modest 5-year survival rates. Immune therapy has offered new
options for HNSCC patients; treatment with T cell checkpoint inhibitors has led to gains in survival for 20-30% of
treated patients. However, the majority of HNSCC patients are resistant to T cell checkpoint inhibitors. Improved
therapeutic approaches that target additional mechanisms of immune escape are needed for this disease. Our
studies show that immune suppressive Tumor Associated Macrophages (TAMs) promote HNSCC immune
escape. We discovered that both tissue resident macrophages (TRM) and bone marrow derived macrophages
(BMDM) accumulate in HPV+ and HPV- HNSCC tumors, where they play distinct roles in promoting immune
suppression but also offer distinct vulnerabilities that can be targeted to promote tumor eradication. Targeting
proliferation pathways suppressed TRM accumulation and tumor progression while targeting the myeloid cell
specific phosphatidylinositol-4,5-bisphosphate 3-kinase isoform gamma (PI3Kg) suppressed BMDM
accumulation. Furthermore, PI3Kg inhibition promoted pro-inflammatory macrophage polarization that
synergized with checkpoint inhibitors to enhance recruitment and activation of cytotoxic CD8+ T cells, leading to
tumor eradication. These results indicated that therapeutic strategies that target TAMs as well as T cell
checkpoints could improve HNSCC patient outcomes. Biomarker studies in clinical trials showed that PI3Kg
antagonism stimulated enhanced T cell recruitment and activation in HNSCC patients. Therefore, we propose to
test the overall hypothesis that therapeutic strategies that block macrophage accumulation and immune
suppression will improve therapeutic outcomes in HNSCC disease. The specific aims of this proposal are: 1) To
identify and target mechanisms controlling macrophage accumulation in HNSCC tumors. 2) To determine how
macrophage plasticity can be harnessed to inhibit HNSCC tumor progression. 3) To develop novel immune
therapeutic strategies and immune biomarkers for HNSCC disease.

## Key facts

- **NIH application ID:** 10694214
- **Project number:** 5R01DE027325-07
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Judith A VARNER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $498,386
- **Award type:** 5
- **Project period:** 2017-09-15 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10694214

## Citation

> US National Institutes of Health, RePORTER application 10694214, Targeting the innate immune response in HNSCC (5R01DE027325-07). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10694214. Licensed CC0.

---

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