ZNF689 deficiency promotes intratumor heterogeneity and immunotherapy resistance in triple-negative breast cancer  

作　　者：Li-Ping Ge Xi Jin Ding Ma Zi-Yu Wang Cheng-Lin Liu Chao-Zheng Zhou Shen Zhao Tian-Jian Yu Xi-Yu Liu Gen-Hong Di Zhi-Ming Shao Yi-Zhou Jiang 

机构地区：[1]Key Laboratory of Breast Cancer in Shanghai,Department of Breast Surgery,Precision Cancer Medicine Center,Fudan University Shanghai Cancer Center,Shanghai,China [2]Department of Oncology,Shanghai Medical College,Fudan University,Shanghai,China [3]Human Phenome Institute,Fudan University,Shanghai,China

出　　处：《Cell Research》2024年第1期58-75,共18页细胞研究（英文版）

基　　金：supported by the National Key R&D Program of China(2020YFA0112304);the National Natural Science Foundation of China(82272822,81922048,82341003,82002799,92159301);the Natural Science Foundation of Shanghai(22ZR1479200,23ZR1411800);the Shanghai Key Laboratory of Breast Cancer(12DZ2260100);the SHDC Municipal Project for Developing Emerging and Frontier Technology in Shanghai Hospitals(SHDC12021103);the Youth Talent Program of Shanghai Health Commission(2022YQ012).

摘　　要：Triple-negative breast cancer(TNBC)is an aggressive disease characterized by remarkable intratumor heterogeneity(ITH),which poses therapeutic challenges.However,the clinical relevance and key determinant of ITH in TNBC are poorly understood.Here,we comprehensively characterized ITH levels using multi-omics data across our center’s cohort(n=260),The Cancer Genome Atlas cohort(n=134),and four immunotherapy-treated cohorts(n=109).Our results revealed that high ITH was associated with poor patient survival and immunotherapy resistance.Importantly,we identified zinc finger protein 689(ZNF689)deficiency as a crucial determinant of ITH formation.Mechanistically,the ZNF689–TRIM28 complex was found to directly bind to the promoter of long interspersed element-1(LINE-1),inducing H3K9me3-mediated transcriptional silencing.ZNF689 deficiency reactivated LINE-1 retrotransposition to exacerbate genomic instability,which fostered ITH.Single-cell RNA sequencing,spatially resolved transcriptomics and flow cytometry analysis confirmed that ZNF689 deficiency-induced ITH inhibited antigen presentation and T-cell activation,conferring immunotherapy resistance.Pharmacological inhibition of LINE-1 significantly reduced ITH,enhanced antitumor immunity,and eventually sensitized ZNF689-deficient tumors to immunotherapy in vivo.Consistently,ZNF689 expression positively correlated with favorable prognosis and immunotherapy response in clinical samples.Altogether,our study uncovers a previously unrecognized mechanism underlying ZNF689 deficiency-induced ITH and suggests LINE-1 inhibition combined with immunotherapy as a novel treatment strategy for TNBC.

关 键 词：IMMUNOTHERAPY IMMUNITY inhibited 

分 类 号：R737.9[医药卫生—肿瘤]