复旦大学江一舟等研究人员合作发现，ZNF689缺乏会促进三阴性乳腺癌的瘤内异质性和免疫疗法耐受性。2024年1月2日，《细胞研究》杂志在线发表了这项成果。

研究人员利用多组学数据全面描述了中心队列（n=260）、癌症基因组图谱队列（n=34）和四个免疫疗法队列（n=109）中的肿瘤内异质性（ITH）水平。研究结果表明，高ITH与患者生存率低和免疫治疗耐药有关。重要的是，研究人员发现锌指蛋白689（ZNF689）缺乏是ITH形成的关键决定因素。

从机制上讲，研究人员发现ZNF689-TRIM28复合物可直接与长穿插元件-1（LINE-1）的启动子结合，诱导H3K9me3介导的转录沉默。ZNF689的缺乏重新激活了LINE-1的逆转录，加剧了基因组的不稳定性，从而促进了ITH的发生。单细胞RNA测序、空间分辨转录组学和流式细胞术分析证实，ZNF689缺乏诱导的ITH抑制了抗原递呈和T细胞活化，从而导致免疫疗法耐药。对LINE-1的药理抑制可显著降低ITH，增强抗肿瘤免疫力，并最终使ZNF689缺陷肿瘤对体内免疫疗法敏感。一致的是，ZNF689的表达与临床样本的良好预后和免疫治疗反应呈正相关。

总之，这项研究揭示了ZNF689缺乏诱导ITH的一种之前未被认识的机制，并建议将LINE-1抑制与免疫疗法相结合作为三阴性乳腺癌（TNBC）的一种新型治疗策略。

据介绍，TNBC是一种侵袭性疾病，其特点是显著的ITH，这给治疗带来了挑战。然而，人们对TNBC中ITH的临床相关性和关键决定因素知之甚少。

附：英文原文

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

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

Issue&Volume: 2024-01-02

Abstract: 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.

DOI: 10.1038/s41422-023-00909-w

Source: https://www.nature.com/articles/s41422-023-00909-w