Wang Zehao, Wang Yanhui, Gao Zhishuang, Zhou Yue, Chen Xiaoting, Xu Rui, Zhao Yangsiyuan, Zhang Yi, Xiu Bingqiu, Liu Jing, Shao Zhiming, Gu Shengmei, Xue Jingyan, Wu Jiong
Department of Breast Surgery, Key Laboratory of Breast Cancer, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
Biomark Res. 2025 Jun 10;13(1):83. doi: 10.1186/s40364-025-00797-9.
Anthracycline-based chemotherapy, while foundational in breast cancer treatment, confers substantial cardiotoxicity. Identifying biomarkers to guide anthracycline exemption without compromising efficacy has remained an unresolved clinical challenge for decades.
We conducted multi-cohort spatial-omics and clinical validation integrating 345 early-stage triple-negative breast cancer (eTNBC) and 167 HER2 + breast cancer patients from Fudan University Shanghai Cancer Center (FUSCC) cohorts, alongside 150 eTNBC patients from a validation cohort. Tumor-specific MHC-II (tsMHC-II) expression was quantified via multiplex immunohistochemistry (mIHC). Mechanistic insights were derived from the NeoTRIP immunotherapy spatial cohort, I-SPY2 trial data, TCGA database, ATAC-seq chromatin profiling, ChIP, and patient-derived organoid (PDO)-immune cell co-culture systems.
In eTNBC, high tsMHC-II expression predicted improved disease-free survival (DFS) and comparable overall survival (OS) with paclitaxel-carboplatin (PCb) versus anthracycline-sequential paclitaxel (EC-P), identifying tsMHC-II as a predictive marker for anthracycline exemption. High tsMHC-II correlated with prolonged DFS and OS in both TNBC and HER2 + subtypes. Multi-omics including spatial and transcriptional cohorts revealed tsMHC-II-high tumors harbor immune-rich microenvironments with elevated cytotoxic T cells, B cells, and antigen-presenting cells. Validation in NeoTRIP and I-SPY2 cohorts demonstrated superior immunotherapy response in tsMHC-II-high patients. Mechanistically, ATAC-seq, ChIP and PDO co-culture models confirmed that KAT2B upregulated tsMHC-II via CIITA promoter acetylation, sustaining immunotherapeutic vulnerability.
TsMHC-II serves as a dual biomarker for adjuvant anthracycline chemotherapy exemption and neoadjuvant immunotherapy stratification in TNBC, driven by KAT2B-mediated epigenetic remodeling. These findings advance precision strategies to reduce anthracycline toxicity while enhancing immune activation in eTNBC.
基于蒽环类药物的化疗虽然是乳腺癌治疗的基础，但会带来严重的心脏毒性。几十年来，在不影响疗效的情况下识别指导豁免蒽环类药物使用的生物标志物一直是一个未解决的临床挑战。
我们进行了多队列空间组学和临床验证，纳入了来自复旦大学附属肿瘤医院（FUSCC）队列的345例早期三阴性乳腺癌（eTNBC）患者和167例HER2+乳腺癌患者，以及来自一个验证队列的150例eTNBC患者。通过多重免疫组化（mIHC）对肿瘤特异性MHC-II（tsMHC-II）表达进行定量。从NeoTRIP免疫治疗空间队列、I-SPY2试验数据、TCGA数据库、ATAC-seq染色质分析、ChIP以及患者来源的类器官（PDO）-免疫细胞共培养系统中获得机制性见解。
在eTNBC中，高tsMHC-II表达预示着无病生存期（DFS）改善，且与紫杉醇-卡铂（PCb）相比，总体生存期（OS）与蒽环类药物序贯紫杉醇（EC-P）相当，这表明tsMHC-II是豁免蒽环类药物使用的预测标志物。高tsMHC-II与TNBC和HER2+亚型的DFS延长和OS延长相关。包括空间和转录组队列在内的多组学研究表明，tsMHC-II高表达的肿瘤具有富含免疫细胞的微环境，其中细胞毒性T细胞、B细胞和抗原呈递细胞增多。在NeoTRIP和I-SPY2队列中的验证表明，tsMHC-II高表达的患者对免疫治疗反应更佳。从机制上讲，ATAC-seq、ChIP和PDO共培养模型证实，KAT2B通过CIITA启动子乙酰化上调tsMHC-II，维持免疫治疗敏感性。
TsMHC-II作为TNBC辅助蒽环类化疗豁免和新辅助免疫治疗分层的双重生物标志物，由KAT2B介导的表观遗传重塑驱动。这些发现推进了精准策略，以降低蒽环类药物毒性，同时增强eTNBC中的免疫激活。
