# P3: Molecular Mechanisms Underlying Therapy Response to Radiation and Immune Checkpoint BlockadeýSUBAWARD

> **NIH NIH U54** · CLEVELAND CLINIC LERNER COM-CWRU · 2022 · $236,408

## Abstract

PROJECT SUMMARY
Research Project 3
 Approximately 75% of head and neck squamous cell carcinoma (HNSCC) patients are treated with
radiation therapy, highlighting the significance of this treatment modality for HNSCC. Unfortunately, 30-40% of
HNSCC patients recur locoregionally due to radioresistance. Due to limited available data derived from intact
human tumors, the biological determinants of how HNSCC respond and adapt to radiation therapy and its
combination with chemotherapy and/or immunotherapy are not well understood. Thus, there is an urgent need
to elucidate the biological basis of how patients respond to radiation-based therapies so that this knowledge can
be exploited to improve eradication of HNSCC and mitigate toxicity to normal tissues. This proposal will leverage
the longitudinal collection of biospecimens and multimodal data from both a completed and proposed Molecular
Characterization Trial of intensity modulated radiation therapy (IMRT) re-irradiation with concurrent and adjuvant
cisplatin or nivolumab, a PD-1 inhibitor, in patients with locoregionally recurrent HNSCC. Radiation therapy
works, at least in part, by damaging DNA and activating the immune system. The DNA damage response (DDR)
plays a critical role in this nexus by governing the resistance of HNSCC to radiation therapy and to immune
checkpoint inhibition (ICI). Significantly, DDR genes are frequently altered in HNSCC. Our preliminary data
suggest: 1) a dynamic regulation of radiation resistance by the DDR, 2) DDR dysregulation is associated with
improved ICI response due to increased tumor mutational burden and alterations in intra-tumoral immune
populations, 3) presence of a unique tumor antigen-specific progenitor CD8+ T-cell subset (PD-1+ TCF-1+) in
HNSCC, which may be stimulated to differentiate into terminal effectors capable of tumor killing by enhanced neo-
antigen presentation by APCs that is further driven by DDR dysregulation. However, the precise mechanisms by
which DDR directs these immunologic dynamics and response to radiation with ICI are unclear. We hypothesize
that key DDR driver proteins govern the intrinsic to acquired resistance of HNSCC to radiation therapy with
chemotherapy and/or ICI. We propose to: 1) Elucidate the genetic and microenvironmental factors that govern
response and resistance to radiation therapy with chemotherapy versus radiation therapy with ICI in HNSCC, 2)
Delineate the molecular mechanisms by which the DDR directs immunological dynamics underlying therapy
response to radiation with ICI, 3) Determine the molecular mechanisms driving acquired resistance in HNSCC
treated with radiation therapy plus ICI versus cisplatin. Completion of this work will elucidate the unique genetic
and microenvironmental factors governing the continuum of intrinsic to acquired resistance of HNSCC to
radiation therapy with chemotherapy versus radiation therapy with ICI, provide a detailed mechanistic
understanding of how key DDR driver proteins govern ...

## Key facts

- **NIH application ID:** 10526305
- **Project number:** 1U54CA274513-01
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** David Sung-wen Yu
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $236,408
- **Award type:** 1
- **Project period:** 2022-09-14 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10526305

## Citation

> US National Institutes of Health, RePORTER application 10526305, P3: Molecular Mechanisms Underlying Therapy Response to Radiation and Immune Checkpoint BlockadeýSUBAWARD (1U54CA274513-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10526305. Licensed CC0.

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