基于 DNA 超分子水凝胶的保护性 NK 细胞储库用于增强三阴性乳腺癌治疗
Protective NK Cell Reservoir Based on DNA Supramolecular Hydrogel for Enhanced Triple-Negative Breast Cancer Therapy.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
CDK4/6 抑制剂与放疗协同启动肿瘤微环境并增强三阴性乳腺癌中抗 PD-L1 免疫治疗的抗肿瘤效应
英文原题：CDK4/6 inhibitors synergize with radiotherapy to prime the tumor microenvironment and enhance the antitumor effect of anti-PD-L1 immunotherapy in triple-negative breast cancer.
查看英文原题
CDK4/6 inhibitors synergize with radiotherapy to prime the tumor microenvironment and enhance the antitumor effect of anti-PD-L1 immunotherapy in triple-negative breast cancer.
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研究概要
CDK4/6 抑制剂联合 RT 增强了 aPD-L1 免疫治疗对 TNBC 的抗肿瘤效果。
中文摘要
背景
三阴性乳腺癌（TNBC）在所有乳腺癌亚型中死亡率最高。免疫治疗虽有前景，但疗效不一。CDK4/6 抑制剂可增强放射敏感性并调节免疫系统，高剂量放疗（RT）也可增强免疫治疗效果。本研究探索将 RT 与 CDK4/6 抑制剂联合，通过调节肿瘤微环境改善 TNBC 免疫治疗。
方法
在 3 种人 TNBC 细胞系（MDA-MB-231、MDA-MB-453、MDA-MB-468）和 2 种小鼠 TNBC 细胞系（4T1、EMT6）中，采用克隆形成实验评估 abemaciclib（CDK4/6 抑制剂）的放射增敏作用。随后在免疫健全的 4T1 和 EMT6 细胞系来源小鼠模型中，评估对照、RT、abemaciclib、抗 PD-L1 抗体（aPD-L1）、abemaciclib 联合 aPD-L1、abemaciclib 联合 RT、aPD-L1 联合 RT，以及 abemaciclib+aPD-L1+RT 三联方案的抗肿瘤疗效。监测小鼠血液 IFN-γ 水平评估免疫应答，并通过流式细胞术和免疫组织化学分析 TIL。
结果
克隆形成实验显示，RT 与 abemaciclib 在所有 TNBC 细胞系中均有协同作用。RT 提高 PD-L1 表达，abemaciclib 则未改变其表达。在 4T1 和 EMT6 小鼠模型中，三联方案显著抑制肿瘤生长（P < 0.01）。在 4T1 模型中，三联组循环 IFN-γ 水平显著高于其他组（P < 0.001）。TIL 分析显示，三联治疗组 CD4⁺、CD8⁺ T 细胞及肿瘤相关巨噬细胞显著增加（P < 0.01）。免疫组化进一步证实，该组肿瘤微环境中 CD4⁺、CD8⁺ T 细胞、单核细胞趋化蛋白-1、CD80⁺ 和 iNOS⁺ 巨噬细胞浸润增加，而 CD206⁺ 巨噬细胞显著减少。
结论
CDK4/6 抑制剂联合 RT 可增强 aPD-L1 对 TNBC 的抗肿瘤作用。该效应与 IFN-γ 分泌增加、CD4⁺ 和 CD8⁺ T 细胞以及 M1 肿瘤相关巨噬细胞募集相关，从而调节肿瘤微环境。
展开英文摘要原文
BACKGROUND
Triple-negative breast cancer (TNBC) has the highest mortality rate among all breast cancer subtypes. Although immunotherapy shows promise, its efficacy varies. CDK4/6 inhibitors can radiosensitize and modulate the immune system, and high-dose radiotherapy (RT) can enhance the effects of immunotherapy. This study explored the combination of RT with CDK4/6 inhibitors to improve TNBC immunotherapy by modulating the tumor microenvironment.
METHODS
We assessed the radiosensitizing effects of abemaciclib (a CDK4/6 inhibitor) using clonogenic assays in three human TNBC cell lines (MDA-MB-231, MDA-MB-453, and MDA-MB-468) and two murine TNBC cell lines (4T1 and EMT6). The antitumor efficacy of the treatments (control, RT, abemaciclib, anti-PD-L1 antibody [aPD-L1], abemaciclib combined with aPD-L1, abemaciclib combined with RT, aPD-L1 combined with RT, and the triple combination of abemaciclib with aPD-L1 and RT) was evaluated in both 4T1 and EMT6 cell line-derived immunocompetent mouse models. Interferon- (IFN- ) levels in mouse blood were monitored to gauge the immune response. Tumor-infiltrating lymphocytes (TILs) were analyzed using flow cytometry and immunohistochemical staining.
RESULTS
Clonogenic assays showed synergistic effects of RT and abemaciclib in all TNBC cell lines. RT increased PD-L1 expression, whereas abemaciclib did not alter PD-L1 expression. In the 4T1 and EMT6 mouse models, the triple combination treatment markedly inhibited tumor growth (P < 0.01). In the 4T1 mouse model, the triple combination group exhibited significantly greater circulating IFN- levels (P < 0.001) than the other groups. TIL analysis revealed a significant increase in CD4 + and CD8 + T cells and tumor-associated macrophages (P < 0.01) in the triple combination therapy group. Immunohistochemical staining confirmed increased infiltration of CD4 + T cells, CD8 + T cells, monocyte chemoattractant protein-1, CD80-, and iNOS- positive macrophages into the tumor microenvironment of this group, with a marked reduction in CD206-positive macrophages.
CONCLUSION
Combining CDK4/6 inhibitors with RT enhanced the antitumor effects of aPD-L1 immunotherapy against TNBC. This effect was correlated with increased IFN- secretion and recruitment of CD4 + and CD8 + T cells and M1 tumor-associated macrophages, leading to modulation of the tumor microenvironment.
论文信息
- 作者
- Yang WC、Wei MF、Shen YC、Huang CS、Kuo SH
- 第一作者单位
- Division of Radiation Oncology, Department of Oncology, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei, 100, Taiwan.Taiwan
- 通讯作者单位
- Division of Radiation Oncology, Department of Oncology, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei, 100, Taiwan. shkuo101@ntu.edu.tw.Taiwan
- 期刊
- Journal of biomedical science2025 Aug 20
- 原文标识
- PubMed 40836337 · DOI 10.1186/s12929-025-01173-3
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