Immunopeptidomics combined with full-length transcriptomics uncovers diverse neoantigens
Neoantigens are crucial for antitumor immunity and immune checkpoint inhibitor (ICI) efficacy by triggering strong immune responses. However, conventional methods for identifying neoantigens, such as whole-exon sequencing and short-read RNA sequencing (RNA-seq), appear to be insufficient, and the tumor mutational burden cannot sufficiently predict ICI efficacy. In this study, we employed a proteogenomic approach using long-read RNA-seq with Pacific Biosciences Single-Molecule Real-Time Sequencing technology to analyze full-length transcripts in combination with the human leukocyte antigen ligandome. As a result, many neoantigen candidates were identified, which were unregistered in a comprehensive database, including those from non-coding regions. Additionally, we validated the responses of specific T cell receptors (TCRs) to these candidates and identified several pairs of TCRs and neoantigens. These findings highlight the presence of more diverse neoantigens than expected that cannot be identified by conventional methods.
Authors
- Vitaly Kochin
- Takamasa Ishino (ORCID: https://orcid.org/0000-0002-8601-0677)
- Shinichi Morishita
- Katsushige Kawase (ORCID: https://orcid.org/0000-0001-6998-8481)
- Kazuo Yamashita (ORCID: https://orcid.org/0000-0002-7825-4719)
- Wenhao Zhou (ORCID: https://orcid.org/0000-0001-8814-2385)
- Yutaka Suzuki (ORCID: https://orcid.org/0000-0002-2603-5688)
- Takashi Inozume (ORCID: https://orcid.org/0000-0001-7054-1863)
- Youki Ueda (ORCID: https://orcid.org/0000-0002-2627-8524)
- Takehiro Ohnuma (ORCID: https://orcid.org/0009-0005-4223-4547)
- Tatsuyoshi Kawamura (ORCID: https://orcid.org/0000-0003-4008-2322)
- Naoya Kato (ORCID: https://orcid.org/0000-0001-8233-5426)
- Tomofumi Watanabe (ORCID: https://orcid.org/0000-0003-4759-7871)
- Takayuki Kanaseki (ORCID: https://orcid.org/0000-0001-7294-6880)
- Yin Min Thu (ORCID: https://orcid.org/0009-0004-9005-2943)
- Motoo Araki (ORCID: https://orcid.org/0000-0002-3172-2482)
- Takamitsu Matsuzawa (ORCID: https://orcid.org/0000-0002-8221-2394)
- Yosuke Togashi
- Toshihiko Torigoe (ORCID: https://orcid.org/0000-0002-9463-5917)
- Joji Nagasaki (ORCID: https://orcid.org/0000-0003-0945-5469)
- Yu Kawahara
- Shinya Kojima
- Yuta Suzuki
- Jun Koseki
- Hiroyoshi Nishikawa
- Masahito Kawazu
- Serina Tokita
- Jason Lin
- Teppei Shimamura
- Toshihide Ueno
- Akiko Honobe-Tabuchi
- Yuka Takano
- Chie Owa
- Hiroyuki Mano
Institutions
- Tokyo Medical and Dental University (JP)
- Sapporo Medical University (JP)
- Tokyo University of Information Sciences (JP)
- Chiba University (JP)
- Okayama University (JP)
- Nagoya City University (JP)
- Okayama University Hospital (JP)
- Chiba Cancer Center (JP)
- TagCyx Biotechnologies (Japan) (JP)
- Kumamoto Orthopedic Surgery Hospital (JP)
- National Cancer Research Institute (GB)
- Nagoya University (JP)
- University of Yamanashi (JP)
- The University of Tokyo (JP)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-12-24
- DOI
- https://doi.org/10.1016/j.celrep.2025.116781
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 0.00