Translation dysregulation in cancer as a source for targetable antigens

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; Nofar Gumpert; Weiwen Yang; Dmitry Alexeev; Pelgia Kyriakidou; Winnie Yao; Mirie Zerbib; Polina Greenberg; Gil Benedek; Kevin Litchfield; Ekaterina Petrovich-Kopitman; Adi Nagler; Roni Oren; Shifra Ben-Dor; Yishai Levin; Yitzhak Pilpel; Marina Rodnina; Jürgen Cox; Yifat Merbl; Ansuman T. Satpathy; Yaron Carmi; Florian Erhard; Tsutomu Suzuki; Allen R. Buskirk; Johanna Olweus; Eytan Ruppin; Andreas Schlosser; Yardena Samuels

doi:10.1016/j.ccell.2025.03.003

Translation dysregulation in cancer as a source for targetable antigens

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

Nofar Gumpert, Weiwen Yang, Dmitry Alexeev, Pelgia Kyriakidou, Winnie Yao, Mirie Zerbib, Polina Greenberg, Gil Benedek, Kevin Litchfield, Ekaterina Petrovich-Kopitman, Adi Nagler, Roni Oren, Shifra Ben-Dor, Yishai Levin, Yitzhak Pilpel, Marina Rodnina, Jürgen Cox, Yifat Merbl, Ansuman T. Satpathy, Yaron Carmi, Florian Erhard, Tsutomu Suzuki, Allen R. Buskirk, Johanna Olweus, Eytan Ruppin, Andreas Schlosser, Yardena Samuels^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

8 Citations (Scopus)

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.

Original language	English
Pages (from-to)	823-840.e18
Journal	Cancer Cell
Volume	43
Issue number	5
Early online date	27 Mar 2025
DOIs	https://doi.org/10.1016/j.ccell.2025.03.003
Publication status	Published - 12 May 2025

Funding

Y. Samuels is supported by the Israel Science Foundation grant no. 2133/23, the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (#770854), the European Union (#101094980), MRA (#917324), the Minerva Stiftung with the funds from the BMBF of the Federal Republic of Germany, the ICRF (20-802-ICG), and the Intramural Research Program of the NIH, NCI. Y. Samuels is the incumbent of the Knell Family Professorial Chair and is the Head of the Moross Integrated Cancer Center (MICC), de-Picciotto-Lesser Cell Observatory unit at MICC. S.G. is supported by the Sheba-Talpiot Medical Program. D.M. is supported by the Israeli Ministry of Aliyah and Integration. C.S.M. is a Cancer Research Institute Irvington Fellow (CRI Award #4134) and a Parker Institute for Cancer Immunotherapy Scholar. A.T.S. is supported by a Career Award for Medical Scientists from the Burroughs Wellcome Fund, a Lloyd J. Old STAR Award from the Cancer Research Institute, a Pew-Stewart Scholars for Cancer Research Award, and the Parker Institute for Cancer Immunotherapy. J.O. is supported by the Research Council of Norway through its Centers of Excellence scheme, #332727, and through grant #316060, and by the Norwegian Cancer Society grant #216135-2020, South-Eastern Regional Health Authority Norway #2021074, ERC under the European Union's Horizon 2020 research and innovation programme (#865805), and Novo Nordisk Foundation. A.R.B. was supported by NIH grant GM136960. T.S. was supported by the Exploratory Research for Advanced Technology (ERATO, JPMJER2002) program from JST.

All Science Journal Classification (ASJC) codes

Oncology
Cancer Research

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Weller, C., Bartok, O., McGinnis, C. S., Palashati, H., Chang, T. G., Malko, D., Shmueli, M. D., Nagao, A., Hayoun, D., Murayama, A., Sakaguchi, Y., Poulis, P., Khatib, A., Erlanger Avigdor, B., Gordon, S., Cohen Shvefel, S., Zemanek, M. J., Nielsen, M. M., Boura-Halfon, S., ... Samuels, Y. (2025). Translation dysregulation in cancer as a source for targetable antigens. Cancer Cell, 43(5), 823-840.e18. https://doi.org/10.1016/j.ccell.2025.03.003

@article{5886087d679e4222b3fae9b75347283f,

title = "Translation dysregulation in cancer as a source for targetable antigens",

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.",

author = "Chen Weller and Osnat Bartok and McGinnis, \{Christopher S.\} and Heyilimu Palashati and Chang, \{Tian Gen\} and Dmitry Malko and Shmueli, \{Merav D.\} and Asuteka Nagao and Deborah Hayoun and Ayaka Murayama and Yuriko Sakaguchi and Panagiotis Poulis and Aseel Khatib and \{Erlanger Avigdor\}, Bracha and Sagi Gordon and \{Cohen Shvefel\}, Sapir and Zemanek, \{Marie J.\} and Nielsen, \{Morten M.\} and Sigalit Boura-Halfon and Shira Sagie and Nofar Gumpert and Weiwen Yang and Dmitry Alexeev and Pelgia Kyriakidou and Winnie Yao and Mirie Zerbib and Polina Greenberg and Gil Benedek and Kevin Litchfield and Ekaterina Petrovich-Kopitman and Adi Nagler and Roni Oren and Shifra Ben-Dor and Yishai Levin and Yitzhak Pilpel and Marina Rodnina and J{\"u}rgen Cox and Yifat Merbl and Satpathy, \{Ansuman T.\} and Yaron Carmi and Florian Erhard and Tsutomu Suzuki and Buskirk, \{Allen R.\} and Johanna Olweus and Eytan Ruppin and Andreas Schlosser and Yardena Samuels",

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month = may,

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doi = "10.1016/j.ccell.2025.03.003",

language = "English",

volume = "43",

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Weller, C , Bartok, O, McGinnis, CS, Palashati, H, Chang, TG, Malko, D , Shmueli, MD, Nagao, A, Hayoun, D, Murayama, A, Sakaguchi, Y, Poulis, P, Khatib, A, Erlanger Avigdor, B, Gordon, S, Cohen Shvefel, S, Zemanek, MJ, Nielsen, MM, Boura-Halfon, S , Sagie, S , Gumpert, N, Yang, W, Alexeev, D, Kyriakidou, P, Yao, W, Zerbib, M, Greenberg, P, Benedek, G, Litchfield, K, Petrovich-Kopitman, E, Nagler, A, Oren, R , Ben-Dor, S , Levin, Y , Pilpel, Y, Rodnina, M, Cox, J, Merbl, Y, Satpathy, AT, Carmi, Y, Erhard, F, Suzuki, T, Buskirk, AR, Olweus, J, Ruppin, E, Schlosser, A & Samuels, Y 2025, 'Translation dysregulation in cancer as a source for targetable antigens', Cancer Cell, vol. 43, no. 5, pp. 823-840.e18. https://doi.org/10.1016/j.ccell.2025.03.003

TY - JOUR

T1 - Translation dysregulation in cancer as a source for targetable antigens

AU - Weller, Chen

AU - Bartok, Osnat

AU - McGinnis, Christopher S.

AU - Palashati, Heyilimu

AU - Chang, Tian Gen

AU - Malko, Dmitry

AU - Shmueli, Merav D.

AU - Nagao, Asuteka

AU - Hayoun, Deborah

AU - Murayama, Ayaka

AU - Sakaguchi, Yuriko

AU - Poulis, Panagiotis

AU - Khatib, Aseel

AU - Erlanger Avigdor, Bracha

AU - Gordon, Sagi

AU - Cohen Shvefel, Sapir

AU - Zemanek, Marie J.

AU - Nielsen, Morten M.

AU - Boura-Halfon, Sigalit

AU - Sagie, Shira

AU - Gumpert, Nofar

AU - Yang, Weiwen

AU - Alexeev, Dmitry

AU - Kyriakidou, Pelgia

AU - Yao, Winnie

AU - Zerbib, Mirie

AU - Greenberg, Polina

AU - Benedek, Gil

AU - Litchfield, Kevin

AU - Petrovich-Kopitman, Ekaterina

AU - Nagler, Adi

AU - Oren, Roni

AU - Ben-Dor, Shifra

AU - Levin, Yishai

AU - Pilpel, Yitzhak

AU - Rodnina, Marina

AU - Cox, Jürgen

AU - Merbl, Yifat

AU - Satpathy, Ansuman T.

AU - Carmi, Yaron

AU - Erhard, Florian

AU - Suzuki, Tsutomu

AU - Buskirk, Allen R.

AU - Olweus, Johanna

AU - Ruppin, Eytan

AU - Schlosser, Andreas

AU - Samuels, Yardena

PY - 2025/5/12

Y1 - 2025/5/12

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/105001399748

U2 - 10.1016/j.ccell.2025.03.003

DO - 10.1016/j.ccell.2025.03.003

M3 - Article

AN - SCOPUS:105001399748

SN - 1535-6108

VL - 43

SP - 823-840.e18

JO - Cancer Cell

JF - Cancer Cell

IS - 5

ER -

Translation dysregulation in cancer as a source for targetable antigens

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