Healthy donor T cell receptors expand functional neoantigen recognition beyond patient vaccination

T cells, emphasizing the critical need for comprehensive functional validation before patient vaccination. Here, we provide a direct comparison of neoantigen-specific T cell responses between vaccinated patients with cancer and HLA-matched healthy donors. Despite vaccination, patient-derived T cells recognized only a small fraction of predicted neoantigens, whereas healthy donor T cells consistently exhibited broader and more robust neoantigen reactivity. Furthermore, we successfully expanded neoantigen-specific T cells from allogeneic donors, revealing that their T cell receptors (TCRs) can recognize targets that the patient's own T cells fail to engage with, partly due to poor T cell fitness. Collectively, these results indicate that cancer vaccines may be insufficient to overcome intrinsic defects in patient-derived T cell responses, supporting the use of healthy donor-derived TCRs as a complementary approach.

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Publication Details

Journal
Science Advances
Published
2026-04-17
DOI
https://doi.org/10.1126/sciadv.adz1156
Primary Topic
Immunotherapy and Immune Responses
Type
article
Field-Weighted Citation Impact
0.00

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article

Healthy donor T cell receptors expand functional neoantigen recognition beyond patient vaccination

Bettina Lieske, Malini Rethnam, Shuting Han, Han Chong Toh et al.
Science Advances
Immunotherapy and Immune Responses
article

Healthy donor T cell receptors expand functional neoantigen recognition beyond patient vaccination

Bettina Lieske, Malini Rethnam, Shuting Han, Han Chong Toh, Gloryn Chia, Kai-Yin Lee, Gwyneth Shook-Ting Soon, Thamizhanban Manoharan, Who-Whong Wang, Zhewang Lin, Si‐Lin Koo, Ian Jse-Wei Tan, Ker‐Kan Tan, Cyrus Zai Ming Cheng, I L Tan, Choon Kong Yap, Wai‐Kit Cheong, Hong Kai Teo, Bei-En Siew, Soon Chai Loo
article en

Abstract

T cells, emphasizing the critical need for comprehensive functional validation before patient vaccination. Here, we provide a direct comparison of neoantigen-specific T cell responses between vaccinated patients with cancer and HLA-matched healthy donors. Despite vaccination, patient-derived T cells recognized only a small fraction of predicted neoantigens, whereas healthy donor T cells consistently exhibited broader and more robust neoantigen reactivity. Furthermore, we successfully expanded neoantigen-specific T cells from allogeneic donors, revealing that their T cell receptors (TCRs) can recognize targets that the patient's own T cells fail to engage with, partly due to poor T cell fitness. Collectively, these results indicate that cancer vaccines may be insufficient to overcome intrinsic defects in patient-derived T cell responses, supporting the use of healthy donor-derived TCRs as a complementary approach.

Science AdvancesVol. 12(16)
Agency for Science, Technology and Research (SG), National University of Singapore (SG), Singapore Institute of Technology (SG), Duke-NUS Medical School (SG), National Cancer Centre Singapore (SG), National University Hospital (SG), Genome Institute of Singapore (SG)
National Research Foundation Singapore
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Openalex Percentile: Top 21%
Immunotherapy and Immune Responses
DOIOpen Access PDFOpenAlex
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