# Defining features of the neoantigen-specific T cell response against a common EGFR mutation in lung cancer

> **NIH NIH F30** · CASE WESTERN RESERVE UNIVERSITY · 2024 · $53,974

## Abstract

PROJECT SUMMARY/ABSTRACT
Driver mutations confer increased fitness to cancer cells but can also encode neoantigens that stimulate an anti-
cancer immune response. This anti-tumor immunity is mediated primarily by T cell receptor (TCR) recognition of
mutation-derived peptides presented on Human Leukocyte Antigen (HLA) complexes. L858R promotes
unchecked growth and is the most common epidermal growth factor receptor (EGFR) mutation in lung cancer,
accounting for 40% of all observed mutations in the protooncogene. How L858R may stimulate an anti-tumor
immune response is not yet understood. The objective of the proposed work is to understand the mechanisms
through which the EGFR L858R mutation affects tumor biology in provoking anti-tumor immunity. My preliminary
data show that L858R-derived peptides are capable of binding to and stabilizing HLA-A*03:01 and HLA-A*11:01
complexes. In two orthogonal assays, L858R peptide-HLA (pHLA) complexes stimulate CD8+ T cells more
strongly than wild-type EGFR pHLA complexes. Finally, using pHLA multimer flow cytometry, I have identified
CD8+ T cells from healthy donor PBMCs that recognize the L858R pHLA complex through their TCRs. I
hypothesize that the EGFR L858R mutation generates an immunogenic neoantigen that provokes T cell-
mediated anti-tumor immunity due to the high clonality of the mutation. In Aim 1, I will fully define determinants
of L858R immunogenicity by characterizing the EGFR L858R-derived neopeptide and its ability to activate T
cells. I will employ HLA immunoprecipitation coupled to liquid chromatography mass spectrometry to identify the
L858R peptides presented on HLA, determine the relative contributions of CD4+ and CD8+ T cells in the immune
response, and examine exhaustion phenotypes in L858R-specific T cells from patients using single cell RNA
and TCR sequencing. In Aim 2, I will determine the ability of EGFR L858R-specific T cells to suppress tumor
growth. I will also determine how mutation clonality and pHLA expression affect the anti-tumor immune response.
This study employs cutting edge genetic tools and computational approaches to generate a detailed
understanding of adaptive immunity against somatic mutations in tumors. Furthermore, this proposal is tailored
for a physician-scientist in training, as it investigates clinically relevant determinants of a T cell-mediated immune
response against EGFR-mutant cancers, and will inform the development of an adoptive T cell therapy for a
large subset of lung cancer patients.

## Key facts

- **NIH application ID:** 10995102
- **Project number:** 1F30CA294669-01
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Stephen Lee Wang
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $53,974
- **Award type:** 1
- **Project period:** 2024-07-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10995102

## Citation

> US National Institutes of Health, RePORTER application 10995102, Defining features of the neoantigen-specific T cell response against a common EGFR mutation in lung cancer (1F30CA294669-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10995102. Licensed CC0.

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