PO.IM01.02 · 免疫学

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

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

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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