肿瘤细胞治疗研究
英文原题：Overcoming NK cell resistance in triple-negative breast cancer via adcc with a humanized anti-CD147 antibody.
Overcoming NK cell resistance in triple-negative breast cancer via adcc with a humanized anti-CD147 antibody.
这些发现确立了HuM6-1B9作为一种有前景的免疫治疗候选药物，它能够克服免疫抵抗，并通过ADCC选择性消除TNBC细胞，而不增强转移潜能。
三阴性乳腺癌（TNBC）是一种侵袭性强且临床治疗困难的亚型，其特征为雌激素受体、孕激素受体及HER2扩增均缺失，导致预后不良且治疗选择有限。亟需靶向替代分子通路以克服耐药并改善患者预后。CD147已成为与肿瘤进展和免疫逃逸相关的表面标志物。本研究采用流式细胞术分析了乳腺癌细胞系（MCF7、MDA-MB-453、MDA-MB-231和HCC38）中CD147与MHC I类分子——NK 细胞的关键抑制性配体——的表达。评估了人源化抗CD147单克隆抗体（HuM6-1B9）增强抗体依赖性细胞介导的细胞毒性（ADCC）的治疗效果。HuM6-1B9对代表性TNBC细胞系MDA-MB-231（K D = 4.982 nM）和HCC38（K D = 4.523 nM）表现出强结合力。在3D球体模型中，HuM6-1B9显著增强了PBMC介导的ADCC，导致TNBC球体活力明显降低。将CFSE标记的MDA-MB-231和HCC38细胞与原代NK细胞共培养，证实了强效的ADCC，分别达到50%和70%的细胞毒性，尽管MHC I类分子高表达。活细胞成像显示caspase-3/7激活，与NK靶向肿瘤细胞凋亡一致，而CD107a脱颗粒和IFN-γ分泌证实了HuM6-1B9对ADCC增强的功能性贡献。重要的是，HuM6-1B9未促进MDA-MB-231细胞的迁移或侵袭，支持其在转移方面的安全性。总体而言，这些发现确立了HuM6-1B9作为一种有前景的免疫治疗候选药物，它能够克服免疫抵抗，并通过ADCC选择性消除TNBC细胞，而不增强转移潜能。通过整合NK细胞毒性、凋亡和3D肿瘤球体的机制性检测，本研究提供了具有临床相关性的见解，突显了HuM6-1B9在TNBC免疫治疗中的转化潜力。
Triple-negative breast cancer (TNBC) is an aggressive and clinically challenging subtype defined by the absence of estrogen receptor, progesterone receptor, and HER2 amplification, resulting in poor prognosis and limited therapeutic options. Targeting alternative molecular pathways is urgently needed to overcome resistance and improve patient outcomes. CD147 has emerged as surface marker associated with tumor progression and immune evasion. In this study, CD147 and MHC class I-a key inhibitory ligand for natural killer cells-were analyzed in breast cancer cell lines (MCF7, MDA-MB-453, MDA-MB-231, and HCC38) using flow cytometry. The therapeutic efficacy of a humanized anti-CD147 monoclonal antibody (HuM6-1B9) was evaluated for its capacity to potentiate antibody-dependent cellular cytotoxicity (ADCC). HuM6-1B9 demonstrated the strong binding to MDA-MB-231 (K D = 4.982 nM) and HCC38 (K D = 4.523 nM), which are representative TNBC cell lines. In 3D spheroid models, HuM6-1B9 significantly enhanced PBMC-mediated ADCC, leading to a marked reduction in TNBC spheroid viability. Co-culture of CFSE-labeled MDA-MB-231 and HCC38 cells with primary NK cells confirmed robust ADCC, achieving 50% and 70% cytotoxicity, respectively, despite high MHC class I expression. Live-cell imaging demonstrated caspase-3/7 activation consistent with apoptosis in NK-targeted tumor cells, while CD107a degranulation and IFN-γ secretion confirmed the functional contribution of HuM6-1B9 to ADCC enhancement. Importantly, HuM6-1B9 did not promote migration or invasion in MDA-MB-231 cells, supporting its safety profile regarding metastasis. Collectively, these findings establish HuM6-1B9 as a promising immunotherapeutic candidate that overcomes immune resistance and selectively eliminates TNBC cells through ADCC without enhancing metastatic potential. By integrating mechanistic assays of NK cytotoxicity, apoptosis, and 3D tumor spheroids, this study provides clinically relevant insights underscoring the translational potential of HuM6-1B9 in TNBC immunotherapy.
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