HER2 mutation–derived neoantigens in NSCLC as actionable targets for TCR therapy

作者：Amanda Montoya, Hui Nie, Peixin Jiang, Jared Slone, Yulia Shulga, Anika Patel, Prashant Menon, Isabella Polic, Emily Bontekoe, Lingzhi Hong, Minying Zhang, Emane Rose Assita, Sarah Forward, Changsheng Xing, Bo Jiang, Drew C. Deniger, Gregory Lizée, Maura Gillison, Navin Varadarajan, Xiuning Le, Jianjun Zhang, Lydia Kavraki, Sheldon J. J. Kwok, John V. Heymach, Alexandre Reuben · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2026 · DOI：10.64898/2026.07.30.741830 · 研究领域：Cancer Immunotherapy and Biomarkers、CAR-T cell therapy research、Immunotherapy and Immune Responses

Abstract HER2 mutations are oncogenic drivers in 1–6% of non-small cell lung cancers (NSCLC), but therapeutic resistance limits the durability of current HER2-targeted treatments. Here, we identify T-cell receptors (TCRs) targeting recurrent HER2 hotspot mutations as a potential immunotherapeutic strategy for HER2-mutant NSCLC. Using neoepitope prediction and antigen-specific T-cell enrichment, we isolated HLA-A*02:01restricted TCRs recognizing HER2 A775insYVMA, S310F, and G776delinsVC mutations, collectively covering approximately 60% of HER2-mutant NSCLC. These TCRs selectively recognized mutant HER2 epitopes without detectable wild-type reactivity and some displayed cross-recognition of related hotspot variants, expanding the spectrum of targetable tumors. The G776delinsVC-specific TCR also exhibited co-receptorindependent activity showcased by its ability to activate CD4 + T cells. Importantly, timelapse single-cell flow cytometry analyses demonstrated that TCR-engineered T cells repeatedly reacquired activated polyfunctional states following serial antigen stimulation, while serial tumor rechallenge assays confirmed sustained cytotoxic activity across multiple rounds of tumor killing. These findings identify recurrent HER2 mutations as shared immunotherapeutic targets and provide a foundation for the development of TCR-based therapies for HER2-mutant NSCLC.