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

Abstract

HER2 mutations are oncogenic drivers in 1 to 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*02:01 restricted 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 coreceptor independent activity showcased by its ability to activate CD4+ T cells. Importantly, time lapse 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.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 05 Aug 2026.

Stats

1-terrible, 9-excellent. How would you rate this preprint? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.