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

Area of Science:

• Molecular Biology
• Cancer Research
• Immunology

Background:

• Nonsense-mediated mRNA decay (NMD) is a cellular surveillance pathway that degrades aberrant mRNAs and regulates gene expression.
• Cancer cells exploit NMD to manage DNA imbalances and alter antigen presentation, impacting immune evasion.
• The LTO1/YAE1 complex, involved in ribosome biogenesis, was identified as a potential NMD factor.

Purpose of the Study:

• To investigate the roles of the LTO1/YAE1 complex in modulating NMD.
• To determine the impact of LTO1/YAE1 on Major Histocompatibility Complex class I (MHC-I) antigen presentation.
• To explore the therapeutic potential of targeting the LTO1/YAE1-NMD axis in cancer immunotherapy.

Main Methods:

• Utilized CRISPR-Cas9 gene editing for knockouts and overexpression studies of LTO1 and YAE1 in tumor cell lines.
• Assessed NMD and MHC-I expression using reporter assays, flow cytometry, RT-qPCR, mRNA decay assays, and polysome profiling.
• Conducted transcriptomic analyses, T cell co-culture assays, and in vivo mouse models with iron chelators for immunotherapy evaluation.

Main Results:

• LTO1/YAE1 deficiency impaired NMD, leading to overexpression of MHC-I regulators (NLRC5, IRF1, NFκB) and enhanced T cell activation.
• Transcriptomic data showed frequent LTO1/YAE1 overexpression in human cancers, correlating with suppressed MHC-I expression.
• Iron chelators inhibited NMD, upregulated MHC-I, improved CD8+ T cell recognition, and boosted the efficacy of TCR-T and ICB therapies.

Conclusions:

• The LTO1/YAE1 complex plays a novel role in regulating MHC-I expression through NMD.
• This study reveals a significant link between NMD and tumor immunogenicity, impacting antigen presentation and T cell activation.
• Targeting the LTO1/YAE1-NMD pathway offers a promising strategy for enhancing cancer immunotherapies.