魏茨曼科学研究所Yardena Samuels研究团队在研究中取得进展。他们揭示了翻译失调在癌症中作为靶向抗原的来源。相关论文于2025年3月27日发表在《癌细胞》杂志上。

为了研究翻译失调在免疫肿瘤控制中的作用，该团队通过删除肿瘤细胞中tRNA wybutoine (yW)-合成蛋白2 （TYW2）来破坏翻译保真度，并通过免疫肽组学、基因组学和功能分析表征了对翻译保真度和免疫原性的下游影响。这些分析表明TYW2敲除（KO）细胞产生免疫原性框外肽。

此外，TYW2缺失增加肿瘤免疫原性，导致体内抗程序性细胞死亡1 （PD-1）检查点阻断敏感性。重要的是，TYW2表达减少与患者对检查点阻断的反应增加有关。总之，该课题组证明翻译保真度的缺陷驱动肿瘤免疫原性，并可能用于癌症免疫治疗。

据了解，主要组织相容性复合体（MHC）分子呈现的异常肽是肿瘤根除的靶点，因为这些肽可以被T细胞识别为外源。恶性细胞中的蛋白质合成是失调的，这可能导致异常肽的产生和呈现，这些异常肽可以用于基于T细胞的治疗。

附：英文原文

Title: Translation dysregulation in cancer as a source for targetable antigens

Author: 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

Issue&Volume: 2025-03-27

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.

DOI: 10.1016/j.ccell.2025.03.003

Source: https://www.cell.com/cancer-cell/abstract/S1535-6108(25)00082-0