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ORIGINAL RESEARCH article
Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1574955
This article is part of the Research TopicGenetically Engineered T cells and Recombinant Antibodies to Target Intracellular Neoantigens: Current Status and Future DirectionsView all articles
Identification of shared neoantigens derived from frameshift mutations in the APC gene
Provisionally accepted
Peng Zhao1,2,3Clara Effenberger2Saki Matsumoto2Toshihiro Tanaka3,4Yusuke Nakamura1,2
Kazuma Kiyotani1,5*- 1Laboratory of Immunogenomics, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Ibaraki-shi, Osaka, Japan
- 2Project for Immunogenomics, Cancer Precision Medicine Center, Japanese Foundation for Cancer Research, Tokyo, Japan
- 3Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo, Tokyo, Japan
- 4Bioresource Research Support Center, Institute of Science Tokyo, Tokyo, Japan
- 5Japanese Foundation For Cancer Research, Tokyo, Japan
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Recent advances of cancer immunotherapy have identified neoantigens as essential targets for personalized treatments. However, since neoantigens are generally unique in individual cancers, neoantigen therapies that are more broadly applicable are eagerly awaited. Shared neoantigens, derived from recurrent mutations found across multiple patients, are considered to be a challenging, but promising approach. Here we analyzed shared frameshift neoantigens derived from frameshift indels in TCGA exome sequencing data and identified 760 possible recurrent frameshift mutation clusters (FSCs) that share frameshifted open reding frames and premature stop codons. Among them, we investigated FSCs in the APC gene (APC-F2-1472* and APC-F3-1512*) and identified HLA-A*24:02-restricted frameshift neoantigen peptides that elicited specific CD8 + T cell responses. Subsequently we identified their corresponding T cell receptor (TCR) sequences and generated genetically-engineered T cells expressing these APC frameshift neoantigen-specific TCRs. These engineered T cells specifically recognized target cells presenting these neoantigens and cytotoxic activity against them, supporting the therapeutic potential of targeting APC frameshift neoantigens in cancer immunotherapy.This study provides compelling evidence for the development of neoantigen-based therapies targeting common frameshift peptides, offering a promising approach for more effective, relatively broadly applicable immunotherapeutic strategies that could benefit a subset population of cancer patients.
Keywords: cancer immunotherapy, Frameshift indels, Frameshift neoantigen, Shared neoantigens, T cell receptor, TCR-engineered T cells, TCR-T cells
Received: 11 Feb 2025; Accepted: 16 Apr 2025.
Copyright: © 2025 Zhao, Effenberger, Matsumoto, Tanaka, Nakamura and Kiyotani. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Kazuma Kiyotani, Japanese Foundation For Cancer Research, Tokyo, Japan
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