Yang Chenghui, Xu Yiying, Lin Zhongmin, Zhang Anqi, Li Lili, Ye Zhiqiang, Zhang Qiongying, Hu Hanwen, Ren Guohong, Cheng Pu, Wang Zhen, Wang Ouchen
Department of Breast Surgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, PR China; Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, First Affiliated Hospital, Wenzhou Medical University, Wenzhou 325035, PR China.
The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Quzhou 324000, PR China.
Drug Resist Updat. 2025 Sep;82:101261. doi: 10.1016/j.drup.2025.101261. Epub 2025 May 29.
The TCbHP regimen, consisting of combining docetaxel (T), carboplatin (Cb), trastuzumab (H), and pertuzumab (P), is the preferred neoadjuvant treatment for locally advanced human epidermal growth factor 2 (HER2)-positive breast cancer. However, about 40 % of patients develop resistance to this treatment. Adding TKIs like pyrotinib to anti-HER2 antibodies may enhance efficacy and reduce resistance, but the mechanisms are not fully understood.
Imaging mass cytometry (IMC) analyzed tissues from 26 patients treated with NeoPICD (docetaxel, carboplatin, pyrotinib, inetetamab) and 21 patients treated with TCbHP. Cellular changes and spatial relationships were assessed pre- and post-treatment. A co-culture system of tumor cells, fibroblasts, and PBMCs were used to examined cytotoxic T-cell function. A predictive model for treatment outcomes was constructed based on these results.
In TCbHP-sensitive patients, IDOHLA-DR epithelial cells expressing PD-L1 were enriched and interacted with Ki67 T cells and M1 macrophages. In TCbHP-resistant patients, fibroblasts formed a barrier that hindered immune cell access, critical for resistance. NeoPICD disrupted this barrier, enhancing immune cell infiltration and alleviating resistance. Machine learning based on spatial cell architecture can predict treatment outcomes.
Spatial organization of cellular interactions in the tumor microenvironment (TME) provides insights into prognosis beyond pathological subtypes. The role of NeoPICD in disruption of fibroblast barriers and enhancement of immune cell function suggests therapeutic advantages in overcoming resistance to anti-HER2 therapies. This research offers new strategies for precision treatment of locally advanced HER2-positive breast cancer.
由多西他赛（T）、卡铂（Cb）、曲妥珠单抗（H）和帕妥珠单抗（P）组成的TCbHP方案是局部晚期人表皮生长因子2（HER2）阳性乳腺癌的首选新辅助治疗方案。然而，约40%的患者会对这种治疗产生耐药性。在抗HER2抗体中添加吡咯替尼等酪氨酸激酶抑制剂（TKIs）可能会提高疗效并降低耐药性，但其机制尚未完全明确。
成像质谱流式细胞术（IMC）分析了26例接受NeoPICD（多西他赛、卡铂、吡咯替尼、因他他单抗）治疗的患者和21例接受TCbHP治疗的患者的组织。在治疗前后评估细胞变化和空间关系。使用肿瘤细胞、成纤维细胞和外周血单核细胞的共培养系统来检测细胞毒性T细胞功能。基于这些结果构建了治疗结果预测模型。
在对TCbHP敏感的患者中，表达程序性死亡配体1（PD-L1）的IDO HLA-DR上皮细胞富集，并与Ki67 T细胞和M1巨噬细胞相互作用。在对TCbHP耐药的患者中，成纤维细胞形成了阻碍免疫细胞进入的屏障，这对耐药性至关重要。NeoPICD破坏了这一屏障，增强了免疫细胞浸润并减轻了耐药性。基于空间细胞结构的机器学习可以预测治疗结果。
肿瘤微环境（TME）中细胞相互作用的空间组织为病理亚型以外的预后提供了见解。NeoPICD在破坏成纤维细胞屏障和增强免疫细胞功能方面的作用表明其在克服抗HER2治疗耐药性方面具有治疗优势。本研究为局部晚期HER2阳性乳腺癌的精准治疗提供了新策略。
