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      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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          Abstract

          Tumor-associated macrophages (TAMs) have been shown to both aid and hinder tumor growth, with patient outcomes potentially hinging on the proportion of M1, pro-inflammatory/growth-inhibiting, to M2, growth-supporting, phenotypes. Strategies to stimulate tumor regression by promoting polarization to M1 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 towards M1 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 the M1:M2 ratio. To investigate this phenomenon, the response is simulated via the model for a variety of M1:M2 ratios. The modeling indicates that polarization to an all-M1 population may be less effective than a combination of both M1 and M2. 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-tuned M1:M2 ratio that maintains both phenotypes in the tumor microenvironment during treatment.

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          Author and article information

          Journal
          Cancer Immunol. Immunother.
          Cancer immunology, immunotherapy : CII
          Springer Science and Business Media LLC
          1432-0851
          0340-7004
          May 2020
          : 69
          : 5
          Affiliations
          [1 ] Department of Nanomedicine, Houston Methodist Research Institute, R8-213, 6670 Bertner St., Houston, TX, 77030, USA.
          [2 ] Department of Bioengineering, University of Louisville, Louisville, KY, USA.
          [3 ] Pharmaceutical and Drug Industries Research Division, National Research Centre, Giza, Egypt.
          [4 ] Department of Nanomedicine, Houston Methodist Research Institute, R8-213, 6670 Bertner St., Houston, TX, 77030, USA. bgodin@houstonmethodist.org.
          [5 ] Department of Obstetrics and Gynecology, Houston Methodist Hospital, Houston, TX, USA. bgodin@houstonmethodist.org.
          [6 ] Department of Bioengineering, University of Louisville, Lutz Hall 419, Louisville, KY, 40292, USA. hbfrie01@louisville.edu.
          [7 ] James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA. hbfrie01@louisville.edu.
          [8 ] Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, USA. hbfrie01@louisville.edu.
          [9 ] Center for Predictive Medicine, University of Louisville, Louisville, KY, USA. hbfrie01@louisville.edu.
          Article
          10.1007/s00262-020-02504-z NIHMS1558644
          10.1007/s00262-020-02504-z
          7186159
          32036448
          00c13d59-3342-43e1-bb50-ff286ce57057
          History

          Mathematical modeling,computational simulation,Cancer immunotherapy,Nanotherapy,Macrophage polarization,Breast cancer liver metastases

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