Wang Hao, Sun Ji-Feng, Wang Chen, Jiang Zhan-Sheng, Tong Zhong-Sheng
Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin, China.
Tianjin's Clinical Research Center for Cancer, Tianjin, China.
Cancer Rep (Hoboken). 2025 Aug;8(8):e70291. doi: 10.1002/cnr2.70291.
Triple-negative breast cancer (TNBC) presents significant treatment challenges and poor prognosis. While immune checkpoint blockade (ICB) therapy shows promise, patient responses vary widely, highlighting the urgent need for reliable biomarkers to predict efficacy and guide treatment decisions.
This study aims to investigate the role of Major Histocompatibility Complex class II (MHC-II) expression in breast cancer, specifically focusing on its impact on immune evasion, tumor metastasis, and immunotherapy efficacy. The objective is to emphasize the necessity of targeted research in order to enhance therapeutic strategies for TNBC.
We employed Limma for conducting differential expression analysis, clusterProfiler for performing GO and KEGG pathway enrichment analyses, and Mendelian randomization analyses utilizing data from the UK Biobank and GEO data sets. Single-cell sequencing data were analyzed using Scanpy and CellTypist, where UMAP, PCA, and the Leiden algorithm were applied to explore cellular heterogeneity as well as gene expression profiles.
We observed significant differential gene expression between MHC-II-high and MHC-II-low hematopoietic stem cells, which has an impact on immune responses and cancer pathways, particularly in TNBC. Mendelian randomization analysis identified key genes associated with breast cancer risk and PD-L1 status. Additionally, ANXA1 was significantly decreased in expression in breast cancer tissues compared to normal tissues and demonstrated increased expression in nonresponders to PD-1/PD-L1 therapies in TNBC patients, suggesting its potential involvement in immunotherapy resistance despite lacking a direct correlation with overall survival rates.
The findings of this study highlight the potential role of ANXA1 in mediating resistance to PD-1/PD-L1 therapy in breast cancer, which is associated with MHC-II expression. ANXA1 could serve as both a predictive marker for treatment resistance and a therapeutic target to enhance the efficacy of immunotherapy.
三阴性乳腺癌（TNBC）带来了重大的治疗挑战且预后较差。虽然免疫检查点阻断（ICB）疗法显示出前景，但患者反应差异很大，凸显了对可靠生物标志物的迫切需求，以预测疗效并指导治疗决策。
本研究旨在探讨主要组织相容性复合体II类（MHC-II）表达在乳腺癌中的作用，特别关注其对免疫逃逸、肿瘤转移和免疫治疗疗效的影响。目的是强调靶向研究的必要性，以增强TNBC的治疗策略。
我们使用Limma进行差异表达分析，使用clusterProfiler进行GO和KEGG通路富集分析，并利用来自英国生物银行和GEO数据集的数据进行孟德尔随机化分析。使用Scanpy和CellTypist分析单细胞测序数据，应用UMAP、PCA和莱顿算法来探索细胞异质性以及基因表达谱。
我们观察到MHC-II高表达和MHC-II低表达造血干细胞之间存在显著的差异基因表达，这对免疫反应和癌症通路有影响，特别是在TNBC中。孟德尔随机化分析确定了与乳腺癌风险和PD-L1状态相关的关键基因。此外，与正常组织相比，乳腺癌组织中膜联蛋白A1（ANXA1）的表达显著降低，并且在TNBC患者中对PD-1/PD-L1治疗无反应者中其表达增加，这表明尽管它与总生存率没有直接相关性，但它可能参与免疫治疗耐药性。
本研究结果突出了ANXA1在介导乳腺癌对PD-1/PD-L1治疗耐药性中的潜在作用，这与MHC-II表达相关。ANXA1既可以作为治疗耐药性的预测标志物，也可以作为增强免疫治疗疗效的治疗靶点。
