# Analysis of the E7-Mediated Mechanism of MHC Class I Repression in HNSCC

> **NIH NIH F31** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $38,520

## Abstract

Abstract
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer type in the world, and is
responsible for over 8,000 deaths in the United States each year. The number of HNSCC cases caused by
human papilloma virus (HPV) is on the rise, especially in patients 40-65 years old. HPV is currently associated
with 80% of oropharyngeal cancers and 5-10% of HNSCC cases from other sub-sites. High-risk HPV strains,
most commonly HPV16 and HPV18, cause the preponderance of HPV-positive HNSCC. Current data suggests
that in HNSCC, HPV16 limits immune detection by preventing surface presentation of the major
histocompatibility complex class I (MHC-I). In HPV-positive HNSCC, MHC-I surface presentation level is
associated with the cytotoxic T cell-mediated anti-tumor immune response and thus the identification of
strategies to prevent HPV-mediated MHC-I repression may have a significant therapeutic benefit for patients
receiving immunotherapies. There some data that suggest E7 negatively regulates transcription of MHC-I
constituent genes; however, the detailed mechanism of E7-mediated MHC-I repression is poorly characterized.
Here, I have generated two E7-overexpressing HPV-negative HNSCC cell lines and confirmed that E7 protein
downregulates transcription of MHC-I. We have developed systematic and logical approaches including
CRISPR/CAS9 profiling that we propose to leverage to characterize the molecular mechanism(s) by which E7-
represses MHC-I in these models, and HPV+ HNSCC models. Further, we have developed a 3D organoid-based
co-culture assay in which these models are co-cultured with patient-matched peripheral blood mononuclear cells
(PBMCs) to test the functional effects of de-repression of MHC-I expression. My central hypothesis is that
identification of the molecular mechanisms by which HPV16_E7 diminish the expression of MHC-I will
lead to the advancement of therapeutic strategies that enhance tumor cell recognition by activated T-
cells. I will address this hypothesis through the following aims: 1) Detail the molecular mechanism(s) of MHC
locus repression by HPV16_E7 in HNSCC, and 2) Qualify HPV16_E7-dependent MHC class I regulatory
pathways in HNSCC. My long-term goal is to develop new therapeutic approaches that improve the overall
survival of HPV+ patients, and in doing so, I hope to characterize the specific mechanisms by which HPV16_E7
can prevent MHC-I surface expression in HPV-positive HNSCC.

## Key facts

- **NIH application ID:** 10066535
- **Project number:** 1F31DE030000-01
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Elizabeth Gensterblum-Miller
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $38,520
- **Award type:** 1
- **Project period:** 2020-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10066535

## Citation

> US National Institutes of Health, RePORTER application 10066535, Analysis of the E7-Mediated Mechanism of MHC Class I Repression in HNSCC (1F31DE030000-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10066535. Licensed CC0.

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