Nonlinear response to cancer nanotherapy due to macrophage interactions revealed by mathematical modeling and evaluated in a murine model via CRISPR-modulated macrophage polarization
Nonlinear response to cancer nanotherapy due to macrophage interactions revealed by mathematical modeling and evaluated in a murine model via CRISPR-modulated macrophage polarization
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DOI：
10.1007/s00262-020-02504-z
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发表时间：
2020-02
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影响因子：
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通讯作者：
F. Leonard;L. T. Curtis;Ahmed R. Hamed;Carolyn Zhang;E. Chau;D. Sieving;B. Godin;H. Frieboes
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文献类型：
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作者：
F. Leonard;L. T. Curtis;Ahmed R. Hamed;Carolyn Zhang;E. Chau;D. Sieving;B. Godin;H. Frieboes
肿瘤相关巨噬细胞（TAM）已被证明可以帮助和阻碍肿瘤生长，患者结局可能取决于M1（促炎/生长抑制）与M2（生长支持）表型的比例。通过促进极化至M1来刺激肿瘤消退的策略是一种利用免疫系统来增强治疗结果（包括化疗）的新方法。我们最近发现，在乳腺癌肝转移灶（BCLM）中，用载有白蛋白结合紫杉醇（MSV-nab-PTX）的介孔颗粒进行纳米治疗可促进巨噬细胞向M1极化。然而，仍然不清楚基于巨噬细胞表型的调节，肿瘤消退可以最大化到什么程度，特别是对于灌注不良的肿瘤如BCLM。在此，首次采用CRISPR系统在受控的体外环境中永久调节巨噬细胞极化。这使得能够设计3D共培养实验，模拟具有各种比率的极化巨噬细胞的BCLM血管不足环境。我们实施了一个数学框架，以评估纳米粒子介导的化疗与TAM极化。预测响应与M1：M2比率不呈线性相关。为了研究这一现象，通过模型模拟各种ofM 1：M2比的响应。模型表明，极化到一个所有的M1人口可能是不太有效的比m1和m2的组合。CRISPR系统的实验结果证实了这一模型驱动的假设。总而言之，这项研究表明，针对灌注不良肿瘤的纳米颗粒介导的化疗反应可能受益于微调的M1：M2比例，该比例在治疗期间维持肿瘤微环境中的两种表型。
Tumor-associated macrophages (TAMs) have been shown to both aid and hinder tumor growth, with patient outcomes potentially hinging on the proportion ofM1, pro-inflammatory/growth-inhibiting, toM2, growth-supporting, phenotypes. Strategies to stimulate tumor regression by promoting polarization toM1 are a novel approach that harnesses the immune system to enhance therapeutic outcomes, including chemotherapy. We recently found that nanotherapy with mesoporous particles loaded with albumin-bound paclitaxel (MSV-nab-PTX) promotes macrophage polarization towardsM1 in breast cancer liver metastases (BCLM). However, it remains unclear to what extent tumor regression can be maximized based on modulation of the macrophage phenotype, especially for poorly perfused tumors such as BCLM. Here, for the first time, a CRISPR system is employed to permanently modulate macrophage polarization in a controlled in vitro setting. This enables the design of 3D co-culture experiments mimicking the BCLM hypovascularized environment with various ratios of polarized macrophages. We implement a mathematical framework to evaluate nanoparticle-mediated chemotherapy in conjunction with TAM polarization. The response is predicted to be not linearly dependent on theM1:M2 ratio. To investigate this phenomenon, the response is simulated via the model for a variety ofM1:M2 ratios. The modeling indicates that polarization to an all-M1 population may be less effective than a combination of bothM1 andM2. Experimental results with the CRISPR system confirm this model-driven hypothesis. Altogether, this study indicates that response to nanoparticle-mediated chemotherapy targeting poorly perfused tumors may benefit from a fine-tunedM1:M2 ratio that maintains both phenotypes in the tumor microenvironment during treatment.