Translation dysregulation in cancer as a source for targetable antigens
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.
Authors
- Nofar Gumpert (ORCID: https://orcid.org/0009-0004-5589-6008)
- Roni Oren (ORCID: https://orcid.org/0000-0003-1228-412X)
- Tsutomu Suzuki (ORCID: https://orcid.org/0000-0002-9731-1731)
- Florian Erhard (ORCID: https://orcid.org/0000-0002-3574-6983)
- Yitzhak Pilpel (ORCID: https://orcid.org/0000-0003-3200-9344)
- Dmitry B. Malko (ORCID: https://orcid.org/0000-0002-3278-3930)
- Winnie Yao (ORCID: https://orcid.org/0000-0003-1159-5153)
- Polina Greenberg
- Yishai Levin (ORCID: https://orcid.org/0000-0002-7279-0246)
- Kevin Litchfield (ORCID: https://orcid.org/0000-0002-3725-0914)
- Yaron Carmi (ORCID: https://orcid.org/0000-0002-0972-0616)
- Gil Benedek (ORCID: https://orcid.org/0000-0003-3761-9467)
- Johanna Olweus (ORCID: https://orcid.org/0000-0002-1898-3100)
- Marina V. Rodnina (ORCID: https://orcid.org/0000-0003-0105-3879)
- Osnat Bartok
- Weiwen Yang
- Mirie Zerbib (ORCID: https://orcid.org/0009-0008-4074-1344)
- Adi Nagler (ORCID: https://orcid.org/0000-0003-2127-5938)
- Yifat Merbl (ORCID: https://orcid.org/0000-0002-3465-2221)
- Allen R. Buskirk (ORCID: https://orcid.org/0000-0003-2720-6896)
- Yuriko Sakaguchi
- Yardena Samuels (ORCID: https://orcid.org/0000-0002-3349-7266)
- Christopher S. McGinnis (ORCID: https://orcid.org/0000-0001-6923-9341)
- Andreas Schlösser (ORCID: https://orcid.org/0000-0003-0612-9932)
- Asuteka Nagao (ORCID: https://orcid.org/0000-0002-9152-1527)
- Bracha Erlanger Avigdor (ORCID: https://orcid.org/0000-0002-5031-8303)
- Shifra Ben‐Dor (ORCID: https://orcid.org/0000-0001-9604-1939)
- Ansuman T. Satpathy (ORCID: https://orcid.org/0000-0002-5167-537X)
- Marie J. Zemanek (ORCID: https://orcid.org/0009-0000-5401-9100)
- Déborah Hayoun
- Merav D. Shmueli (ORCID: https://orcid.org/0000-0002-9196-7633)
- Heyilimu Palashati (ORCID: https://orcid.org/0000-0001-6903-2180)
- Eytan Ruppin (ORCID: https://orcid.org/0000-0002-7862-3940)
- Panagiotis Poulis (ORCID: https://orcid.org/0009-0004-4117-5904)
- Ayaka Murayama
- Tiangen Chang (ORCID: https://orcid.org/0000-0003-1485-1992)
- Dmitry Alexeev (ORCID: https://orcid.org/0000-0003-0783-1176)
- Ekaterina Petrovich‐Kopitman (ORCID: https://orcid.org/0000-0002-6050-6404)
- Shira Sagie (ORCID: https://orcid.org/0000-0001-7234-0256)
- Sigalit Boura‐Halfon (ORCID: https://orcid.org/0009-0000-9172-0051)
- Sapir Cohen Shvefel
- Morten M. Nielsen (ORCID: https://orcid.org/0000-0001-5432-2396)
- Jürgen Cox
- A. Khatib
- Sagi Gordon
- Chen Weller
- Pelgia Kyriakidou
Institutions
- National Institutes of Health (US)
- Johns Hopkins University (US)
- Tel Aviv University (IL)
- Hebrew University of Jerusalem (IL)
- Johns Hopkins Medicine (US)
- Hadassah Medical Center (IL)
- Max Planck Institute for the Study of Religious and Ethnic Diversity (DE)
- Max Planck Institute of Experimental Medicine (DE)
- National Cancer Institute (US)
- Center for Cancer Research (US)
- Max Planck Institute of Biochemistry (DE)
- Weizmann Institute of Science (IL)
- The University of Tokyo (JP)
Publication Details
- Journal
- Cancer Cell
- Published
- 2025-03-29
- DOI
- https://doi.org/10.1016/j.ccell.2025.03.003
- Citations
- 16
- Primary Topic
- RNA and protein synthesis mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 12.90
Funders
- Cancer Research Institute
- Israel Cancer Research Fund
- Melanoma Research Alliance
- Israel Science Foundation
- Support Center for Advanced Telecommunications Technology Research Foundation
- Horizon 2020 Framework Programme