Chen Weller, Osnat Bartok, Christopher S. McGinnis, Heyilimu Palashati, Tian-Gen Chang, Dmitry Malko, Merav D. Shmueli, Asuteka Nagao, Deborah Hayoun, Ayaka Murayama, Yuriko Sakaguchi, Panagiotis Poulis, Aseel Khatib, Bracha Erlanger Avigdor, Sagi Gordon, Sapir Cohen Shvefel, Marie J. Zemanek, Morten M. Nielsen, Sigalit Boura-Halfon, Shira Sagie, Yardena Samuels
{"title":"Translation dysregulation in cancer as a source for targetable antigens","authors":"Chen Weller, Osnat Bartok, Christopher S. McGinnis, Heyilimu Palashati, Tian-Gen Chang, Dmitry Malko, Merav D. Shmueli, Asuteka Nagao, Deborah Hayoun, Ayaka Murayama, Yuriko Sakaguchi, Panagiotis Poulis, Aseel Khatib, Bracha Erlanger Avigdor, Sagi Gordon, Sapir Cohen Shvefel, Marie J. Zemanek, Morten M. Nielsen, Sigalit Boura-Halfon, Shira Sagie, Yardena Samuels","doi":"10.1016/j.ccell.2025.03.003","DOIUrl":null,"url":null,"abstract":"Aberrant peptides presented by major histocompatibility complex (MHC) molecules are targets for tumor eradication, as these peptides can be recognized as foreign by T cells. Protein synthesis in malignant cells is dysregulated, which may result in the generation and presentation of aberrant peptides that can be exploited for T cell-based therapies. To investigate the role of translational dysregulation in immunological tumor control, we disrupt translation fidelity by deleting tRNA wybutosine (yW)-synthesizing protein 2 (<em>TYW2</em>) in tumor cells and characterize the downstream impact on translation fidelity and immunogenicity using immunopeptidomics, genomics, and functional assays. These analyses reveal that <em>TYW2</em> knockout (KO) cells generate immunogenic out-of-frame peptides. Furthermore, <em>Tyw2</em> loss increases tumor immunogenicity and leads to anti-programmed cell death 1 (PD-1) checkpoint blockade sensitivity <em>in vivo</em>. Importantly, reduced <em>TYW2</em> expression is associated with increased response to checkpoint blockade in patients. Together, we demonstrate that defects in translation fidelity drive tumor immunogenicity and may be leveraged for cancer immunotherapy.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"3 1","pages":""},"PeriodicalIF":48.8000,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer Cell","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.ccell.2025.03.003","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Aberrant peptides presented by major histocompatibility complex (MHC) molecules are targets for tumor eradication, as these peptides can be recognized as foreign by T cells. Protein synthesis in malignant cells is dysregulated, which may result in the generation and presentation of aberrant peptides that can be exploited for T cell-based therapies. To investigate the role of translational dysregulation in immunological tumor control, we disrupt translation fidelity by deleting tRNA wybutosine (yW)-synthesizing protein 2 (TYW2) in tumor cells and characterize the downstream impact on translation fidelity and immunogenicity using immunopeptidomics, genomics, and functional assays. These analyses reveal that TYW2 knockout (KO) cells generate immunogenic out-of-frame peptides. Furthermore, Tyw2 loss increases tumor immunogenicity and leads to anti-programmed cell death 1 (PD-1) checkpoint blockade sensitivity in vivo. Importantly, reduced TYW2 expression is associated with increased response to checkpoint blockade in patients. Together, we demonstrate that defects in translation fidelity drive tumor immunogenicity and may be leveraged for cancer immunotherapy.
期刊介绍:
Cancer Cell is a journal that focuses on promoting major advances in cancer research and oncology. The primary criteria for considering manuscripts are as follows:
Major advances: Manuscripts should provide significant advancements in answering important questions related to naturally occurring cancers.
Translational research: The journal welcomes translational research, which involves the application of basic scientific findings to human health and clinical practice.
Clinical investigations: Cancer Cell is interested in publishing clinical investigations that contribute to establishing new paradigms in the treatment, diagnosis, or prevention of cancers.
Insights into cancer biology: The journal values clinical investigations that provide important insights into cancer biology beyond what has been revealed by preclinical studies.
Mechanism-based proof-of-principle studies: Cancer Cell encourages the publication of mechanism-based proof-of-principle clinical studies, which demonstrate the feasibility of a specific therapeutic approach or diagnostic test.