PO.IM01.02 · 免疫学

肿瘤内在性METTL5通过损害卵巢癌中ATF4的翻译来限制T细胞诱导的铁死亡

Tumor-intrinsic METTL5 restricts T cell-induced ferroptosis by impairing ATF4 translation in ovarian cancer

编号 2915 展板 25 时间 4/20 02:00–05:00 区域 Section 10 主讲 Jiakai Hou, PhD

分会场 Modifiers of Inflammation and the Tumor Microenvironment

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作者与单位 Authors & Affiliations

Jiakai Hou¹, Cheng-wei Ju², Nicholas A. Egan¹, Yanjun Wei³, Yunfei Wang⁴, Minghao Dang⁵, Tianyi Zhou¹, Leilei Shi⁶, Ningbo Zheng¹, Si Chen¹, Ashley Guerrero¹, Xiaofang Liang¹, Wanfu Wu¹, Areej Akhtar¹, Chitra Dhiman¹, Debanwita Roy Burman¹, Andro Gerges¹, Mason D. Flores¹, Han Li², Li-Sheng Zhang², Marleen Kok⁷, Xiaobo Mao⁸, Linghua Wang⁹, Qin Feng¹, Yiwen Chen³, Sanghoon Lee¹⁰, Daniel McGrail¹¹, Nidhi Sahni⁶, Chuan He², Amir A. Jazaeri¹⁰, Weiyi Peng¹

¹Biology and Biochemistry, University of Houston, Houston, TX,²The University of Chicago, Chicago, IL,³Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX,⁴Clinical Science Lab, H. Lee Moﬃtt Cancer Center & Research Institute, Tampa, FL,⁵Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX,⁶Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX,⁷Netherlands Cancer Institute, Amsterdam, Netherlands,⁸Neurology, Johns Hopkins University School of Medicine, Baltimore, MD,⁹Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX,¹⁰Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX,¹¹Cleveland Clinic, Cleveland, OH

摘要 Abstract

中文摘要

为系统性地界定驱动卵巢癌（OC）免疫抵抗的肿瘤内在性机制，我们整合了体外全基因组CRISPR免疫筛选、体内靶向免疫筛选以及对16个已发表ICB患者队列的分析。通过这一流程，筛选出693个候选基因，其中METTL5成为肿瘤内在性免疫逃逸的关键调控因子。泛癌TCGA分析显示，METTL5在多种癌症类型中显著上调，OC在34种恶性肿瘤中表达量位居第二。尽管METTL5表达与OC分期或总生存期无相关性，但较高的表达与细胞溶解活性评分降低密切相关，提示抗肿瘤免疫受到抑制。在MDACC HGSOC队列（NCT03026062）中，基线肿瘤样本中METTL5表达升高的患者在接受ICB治疗后应答显著较差、总生存期较短，支持其临床相关性。在机制上，OC模型中METTL5缺失特异性地降低了18S rRNA A1832位点的m6A甲基化，破坏了螺旋44的结构，损害了核糖体扫描和翻译。基于RiboLace的活性核糖体分析表明，METTL5敲除重编程了翻译，尤其下调了富集于"EIF2AK1对血红素缺乏的应答"通路的基因，这与整合应激反应（ISR）缺陷一致。ATF4的翻译显著减少，同时下游靶点SLC7A11和SLC3A2的表达降低，二者是抑制脂质过氧化和铁死亡的胱氨酸/谷氨酸反向转运体的关键组分。因此，METTL5缺陷的OC细胞表现出脂质过氧化增加，以及在体外和体内对T细胞介导的铁死亡的敏感性增强。重新引入ATF4可恢复SLC7A11/SLC3A2的表达并逆转铁死亡敏感性，而药物抑制铁死亡产生了类似效果。这些发现确定METTL5是OC中ATF4翻译、氧化应激控制和免疫抵抗的核心调控因子。METTL5表达升高可能作为ICB应答不佳的生物标志物。在治疗上，抑制METTL5、抑制ATF4翻译或诱导铁死亡是增强免疫治疗疗效的潜在策略。本研究确立了METTL5-ATF4-铁死亡轴作为免疫逃逸的关键肿瘤内在性机制，并为解读癌症-免疫相互作用提供了一个可推广的框架。

查看英文原文 English abstract

To systematically define tumor-intrinsic mechanisms driving immune resistance in ovarian cancer (OC), we integrated an in vitro genome-wide CRISPR immune screen, in vivo targeted immune screens, and analysis of 16 published ICB patient cohorts. From this pipeline, 693 candidate genes were shortlisted, and METTL5 emerged as a key regulator of tumor-intrinsic immune evasion. Pan-cancer TCGA analysis revealed significant METTL5 upregulation across multiple cancer types, with OC showing the second-highest expression among 34 malignancies. Although METTL5 expression did not correlate with OC stage or overall survival, higher expression was strongly associated with reduced cytolytic activity scores, suggesting suppressed antitumor immunity. In the MDACC HGSOC cohort (NCT03026062), patients with elevated METTL5 expression in baseline tumor samples exhibited significantly poorer responses and shorter overall survival after ICB therapy, supporting its clinical relevance. Mechanistically, METTL5 loss in OC models specifically reduced m 6 A methylation at A1832 of 18S rRNA, disrupting helix 44 structure and impairing ribosomal scanning and translation. RiboLace-based active ribosome profiling demonstrated that METTL5 knockout reprograms translation, notably downregulating genes enriched in the “Response of EIF2AK1 to Heme Deficiency” pathway, consistent with defective integrated stress response (ISR). Translation of ATF4 was markedly reduced, accompanied by decreased expression of downstream targets SLC7A11 and SLC3A2, key components of the cystine/glutamate antiporter that suppress lipid peroxidation and ferroptosis. As a result, METTL5-deficient OC cells displayed increased lipid peroxidation and heightened sensitivity to T cell-mediated ferroptosis in vitro and in vivo . Reintroduction of ATF4 restored SLC7A11/SLC3A2 expression and reversed ferroptosis sensitivity, while pharmacologic inhibition of ferroptosis produced similar effects. These findings identify METTL5 as a central regulator of ATF4 translation, oxidative stress control, and immune resistance in OC. Elevated METTL5 expression may serve as a biomarker for poor ICB response. Therapeutically, METTL5 inhibition, ATF4 translation suppression or ferroptosis induction represent potential strategies to enhance immunotherapy efficacy. This study establishes the METTL5-ATF4-ferroptosis axis as a critical tumor-intrinsic mechanism of immune evasion and provides a generalizable framework for decoding cancer-immune interactions.

利益披露 Disclosure

J. Hou, None.. C. Ju, None.. N. A. Egan, None.. Y. Wei, None.. Y. Wang, None.. M. Dang, None.. T. Zhou, None.. L. Shi, None.. N. Zheng, None.. S. Chen, None.. A. Guerrero, None.. X. Liang, None.. W. Wu, None.. A. Akhtar, None.. C. Dhiman, None.. D. Roy Burman, None.. A. Gerges, None.. M. D. Flores, None.. H. Li, None.. L. Zhang, None. M. Kok, Multiple companies M. Kok reports funding to the institute from BMS, Roche/Genentech, AstraZeneca (AZ), and an advisory role/speaker fee for Alderaan, BMS, Domain Therapeutics, Gilead, Roche, Merck Sharp & Dohme, and Daiichi Sankyo, outside the submitted work.. X. Mao, None.. L. Wang, None.. Q. Feng, None.. Y. Chen, None.. S. Lee, None.. D. McGrail, None.. N. Sahni, None. C. He, Multiple companies C. He is a scientific founder, a member of the scientific advisory board and equity holder of Aferna Bio, Inc. and Ellis Bio Inc., a scientific cofounder and equity holder of Accent Therapeutics, Inc., and a member of the scientific advisory board of Rona Therapeutics and Element Biosciences. A. A. Jazaeri, Multiple companies AA. Jazaeri reports personal consulting fees from Gerson Lehrman Group, Guidepoint, and paid advisory activities (last 2 years) for Iovance advisory board meeting, NuProbe, Simcere, PACT Pharma, Genentech-Roche, Eisai, Agenus, and Macrogenics, Theolytics outside submitted work.. Multiple companies He also reports grant funding to the institution for clinical trials from AstraZeneca, Bristol Myers Squibb (BMS), Iovance, Aravive, Pfizer, Immatics US, Eli Lilly, Merck, Macrogenics and stock/stock options from Avenge Bio outside submitted work.. W. Peng, None.

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