LTO1 and YAE1 regulate MHC-I expression via nonsense-mediated RNA decay in tumor cells

作者：Zhengning Yang, Zhongxuan Meng, Shang-Yuan Liu, Yuxin Chen, Xuhong Gan, Zi‑Mei Zhang, Xiao‐San Luo, Jiahong Yan, Huijin Chen, Danqing Huang, Lihong Huang, Xiaomin Zeng, Wen-yu Ma, Jun Liu, L. Wang, Haotian Huang, Xinyi Yang, Mei Hu, Lin Chen, Hongli Du, Qibin Leng, Li Qiu, Xiaoling Wang · 发表于：Journal for ImmunoTherapy of Cancer · 年份：2025 · DOI：10.1136/jitc-2025-011893 · 被引用次数：2 · 研究领域：RNA Research and Splicing、interferon and immune responses、Cancer-related molecular mechanisms research

Background Nonsense-mediated messenger RNA decay (NMD) is a highly conserved surveillance system that degrades mRNAs with premature termination codons (PTCs), and regulates the mRNA quantity. Cancer cells hijack NMD to compensate for the imbalanced DNA levels and modulate their antigenicity. We identified the LTO1/YAE1 complex as NMD factors regulating ribosome biogenesis. Our study aimed to investigate their roles in modulating NMD and major histocompatibility complex class I (MHC-I) antigen presentation, which is vital for cancer immunotherapy. Methods Clustered regularly interspaced short palindromic repeats (CRISPR) and the CRISPR-associated protein 9 (Cas9)-mediated gene knockouts, overexpression, and mutational analysis were used to explore the role of LTO1 and YAE1 in NMD and MHC-I expression across various tumor cell lines, assayed by fluorescent reporter-based assays, fluorescence-activated cell sorting analysis, reverse transcription-quantitative PCR, mRNA decay assay, and polysome profiling. Transcriptomic analyses were used to assess the expression of LTO1/YAE1 and their correlation with MHC-I molecules in human cancers. T cell receptor (TCR)-T cells and tumor cells coculture were employed to monitor the effect of LTO1 and YAE1 loss on T cell activation. Iron chelators were further tested as NMD inhibitors to enhance cancer immunotherapy using in vitro coculture assay and a mouse tumor model for immune checkpoint blockade (ICB) therapy. Results We demonstrate that...