# Project 1:Therapeutically improving HNSCC antigenicity through epigenetic reprogramming

> **NIH NIH P01** · YALE UNIVERSITY · 2023 · $268,727

## Abstract

SUMMARY
The majority of head and neck squamous cell carcinoma (HNSCC) patients (~80%) do not respond to
immune checkpoint blockade (ICB). Increasing evidence highlights two main barriers to achieving
clinical response with immunotherapy in HNSCC patients: (i) the tumor's overall poor antigenicity,
which limits the generation of antitumor immunity, and (ii) innate and adaptive immune suppressive
mechanisms that result in immune tolerance. The overarching goal of this Program Project (P01) is to
address these two barriers to improve the low response rates of HNSCC to immunotherapy. Projects
1 and 2 focus on reprogramming tumor cell antigenicity using two different but complementary
approaches and Project 3 focuses on converting these antigenic shifts into ones that provoke
successful anti-tumor immunity. This Project (Project 1) focuses on reprogramming the antigenicity of
the cancers through epigenetic therapy with the goal of enhancing overall tumor antigen presentation
and recognition by the immune system. We hypothesize that a DNA methyltransferase inhibitor can
uncover epigenetically silenced genes, such as HLA class I APM components and neoantigens
across and within heterogeneous tumor cell populations, to uniformly improve tumor cell antigenicity,
and, thus, immunogenicity which translates into effective clinical response with immunotherapy. In our
proposal, we leverage a collaborative team science approach with multi-disciplinary expertise in
HNSCC, cancer immunology, cancer genomics, epigenetics, bioinformatics, HLA biology, and antigen
peptide discovery across multiple institutions and an ongoing phase Ib/II investigator-initiated clinical
trial administering a DNA methlytransferase inhibitor in combination with ICB in HNSCC patients.
Utilizing state of the art technology such as DNA methylation, bulk RNASeq and single-cell RNASeq
(scRNASeq) platforms, we plan to comprehensively characterize the pre- and on-treatment biopsy
samples to assess changes in expression levels of the HLA class I APM components and identify a
panel of shared neoantigen(s) expressed within and across HNSCCs in order to determine whether
we are able to successful reprogram the antigenicity of a tumor through epigenetic therapy.

## Key facts

- **NIH application ID:** 10690600
- **Project number:** 7P01CA240239-05
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Sara Isabel Pai
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $268,727
- **Award type:** 7
- **Project period:** 2019-09-19 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10690600

## Citation

> US National Institutes of Health, RePORTER application 10690600, Project 1:Therapeutically improving HNSCC antigenicity through epigenetic reprogramming (7P01CA240239-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10690600. Licensed CC0.

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