Translation dysregulation in cancer as a source for targetable antigens
Chen Weller, Osnat Bartok, Christopher S. McGinnis, Heyilimu Palashati, Tiangen Chang, Dmitry B. Malko, Merav D. Shmueli, Asuteka Nagao, Déborah Hayoun, Ayaka Murayama, Yuriko Sakaguchi, Panagiotis Poulis, A. 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 V. Rodnina, Jürgen Cox, Yifat Merbl, Ansuman T. Satpathy, Yaron Carmi, Florian Erhard, Tsutomu Suzuki, Allen R. Buskirk, Johanna Olweus, Eytan Ruppin, Andreas Schlösser, Yardena Samuels
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.