Radiotherapy Department, University of Florence, 3, Largo Brambilla, 50124, Florence, Italy.
Department of Experimental and Clinical Medicine, Section of Anatomy and Histology, Research Unit of Histology an Embryology, University of Florence, Florence, Italy.
Clin Transl Oncol. 2022 Jul;24(7):1395-1402. doi: 10.1007/s12094-022-02785-z. Epub 2022 Feb 25.
Tumor-associated macrophages (TAM) may participate to antitumor activity of anti-HER2-targeted therapies (Pertuzumab, Trastuzumab) in breast cancers harbouring HER-2 overexpression through antibody-dependent phagocytosis. Additive antitumor effect of concurrent cytotoxic chemotherapies, including Paclitaxel, may be counterbalanced by alteration in TAM infiltrate. The aim of this study is to evaluate the role of TAM in tumor response to anti-HER2-targeted therapies and chemotherapy in an experimental model of HER2-amplified breast cancer.
A xenograft mouse model was built by subcutaneous injection of the SKBR-3 human HER2-amplified breast cancer cell line in Hu-CD34+ mice. Animals were randomized to receive weekly administration of Cremophor (control), Trastuzumab+Pertuzumab (TP), and Paclitaxel+Trastuzumab+Pertuzumab (PTP) with or without macrophage depletion with clodronate (C). At week 4, mice were euthanised and tumors were harvested for immunohistochemical analysis of TAM infiltration (RBP-J CD163 and CD68 for M1, M2, and overall TAM, respectively).
Tumor size was significantly lower in mice treated with TP, PTP, and PTP+C as compared to control, while no meaningful difference was observed in the TP+C arm. Analysis of TAM infiltrate showed significantly lower CD68 and CD163 expression in PTP, TP+C, and PTP+C as compared to TP and control arm. RBP-J expression was significantly decreased in mice treated with clodronate depletion.
Activity of TP is modulated by TAM infiltrate, that is inhibited by concurrent administration of Paclitaxel. To enhance the effect of anti-HER2-targeted therapies and minimize chemotherapy-related side effects, modulation of TAM should be considered in novel therapeutic combinations.
肿瘤相关巨噬细胞（TAM）可能通过抗体依赖的吞噬作用参与乳腺癌中过表达 HER-2 的抗 HER2 靶向治疗（曲妥珠单抗、帕妥珠单抗）的抗肿瘤活性。包括紫杉醇在内的联合细胞毒性化疗的附加抗肿瘤作用可能因 TAM 浸润的改变而被抵消。本研究旨在评估 TAM 在 HER2 扩增乳腺癌的实验模型中对抗 HER2 靶向治疗和化疗的肿瘤反应中的作用。
通过将 SKBR-3 人 HER2 扩增乳腺癌细胞系皮下注射到 Hu-CD34+小鼠中建立异种移植小鼠模型。动物被随机分为每周接受 Cremophor（对照）、曲妥珠单抗+帕妥珠单抗（TP）和紫杉醇+曲妥珠单抗+帕妥珠单抗（PTP）治疗，或用氯膦酸盐（C）进行巨噬细胞耗竭。在第 4 周，处死小鼠并收获肿瘤，用于 TAM 浸润的免疫组织化学分析（RBP-J CD163 和 CD68 分别用于 M1、M2 和总 TAM）。
与对照组相比，TP、PTP 和 PTP+C 治疗的小鼠肿瘤体积明显较小，而 TP+C 组无明显差异。TAM 浸润分析显示，与 TP 和对照组相比，PTP、TP+C 和 PTP+C 组的 CD68 和 CD163 表达明显降低。用氯膦酸盐耗竭处理后，RBP-J 表达明显降低。
TP 的活性受 TAM 浸润的调节，而紫杉醇的联合给药抑制了这种调节。为了增强抗 HER2 靶向治疗的效果并最小化化疗相关的副作用，在新的治疗组合中应考虑 TAM 的调节。
