Nonlinear response to cancer nanotherapy due to macrophage interactions revealed by mathematical modeling and evaluated in a murine model via CRISPR-modulated macrophage polarization

Research output: Contribution to journalArticle

Fransisca Leonard, Louis T. Curtis, Ahmed R. Hamed, Carolyn Zhang, Eric Chau, Devon Sieving, Biana Godin, Hermann B. Frieboes

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.

Original languageEnglish (US)
Pages (from-to)731-744
Number of pages14
JournalCancer Immunology, Immunotherapy
Volume69
Issue number5
DOIs
StatePublished - May 1 2020

PMID: 32036448

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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. / Leonard, Fransisca; Curtis, Louis T.; Hamed, Ahmed R.; Zhang, Carolyn; Chau, Eric; Sieving, Devon; Godin, Biana; Frieboes, Hermann B.

In: Cancer Immunology, Immunotherapy, Vol. 69, No. 5, 01.05.2020, p. 731-744.

Research output: Contribution to journalArticle

Harvard

Leonard, F, Curtis, LT, Hamed, AR, Zhang, C, Chau, E, Sieving, D, Godin, B & Frieboes, HB 2020, 'Nonlinear response to cancer nanotherapy due to macrophage interactions revealed by mathematical modeling and evaluated in a murine model via CRISPR-modulated macrophage polarization' Cancer Immunology, Immunotherapy, vol. 69, no. 5, pp. 731-744. https://doi.org/10.1007/s00262-020-02504-z

APA

Leonard, F., Curtis, L. T., Hamed, A. R., Zhang, C., Chau, E., Sieving, D., ... Frieboes, H. B. (2020). Nonlinear response to cancer nanotherapy due to macrophage interactions revealed by mathematical modeling and evaluated in a murine model via CRISPR-modulated macrophage polarization. Cancer Immunology, Immunotherapy, 69(5), 731-744. https://doi.org/10.1007/s00262-020-02504-z

Vancouver

Leonard F, Curtis LT, Hamed AR, Zhang C, Chau E, Sieving D et al. Nonlinear response to cancer nanotherapy due to macrophage interactions revealed by mathematical modeling and evaluated in a murine model via CRISPR-modulated macrophage polarization. Cancer Immunology, Immunotherapy. 2020 May 1;69(5):731-744. https://doi.org/10.1007/s00262-020-02504-z

Author

Leonard, Fransisca ; Curtis, Louis T. ; Hamed, Ahmed R. ; Zhang, Carolyn ; Chau, Eric ; Sieving, Devon ; Godin, Biana ; Frieboes, Hermann B. / Nonlinear response to cancer nanotherapy due to macrophage interactions revealed by mathematical modeling and evaluated in a murine model via CRISPR-modulated macrophage polarization. In: Cancer Immunology, Immunotherapy. 2020 ; Vol. 69, No. 5. pp. 731-744.

BibTeX

@article{3355ada62735423c8093c64954d29819,
title = "Nonlinear response to cancer nanotherapy due to macrophage interactions revealed by mathematical modeling and evaluated in a murine model via CRISPR-modulated macrophage polarization",
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.",
keywords = "Breast cancer liver metastases, Cancer immunotherapy, Macrophage polarization, Mathematical modeling, Nanotherapy, computational simulation",
author = "Fransisca Leonard and Curtis, {Louis T.} and Hamed, {Ahmed R.} and Carolyn Zhang and Eric Chau and Devon Sieving and Biana Godin and Frieboes, {Hermann B.}",
year = "2020",
month = "5",
day = "1",
doi = "10.1007/s00262-020-02504-z",
language = "English (US)",
volume = "69",
pages = "731--744",
journal = "Cancer Immunology, Immunotherapy",
issn = "0340-7004",
publisher = "Springer Science and Business Media Deutschland GmbH",
number = "5",

}

RIS

TY - JOUR

T1 - Nonlinear response to cancer nanotherapy due to macrophage interactions revealed by mathematical modeling and evaluated in a murine model via CRISPR-modulated macrophage polarization

AU - Leonard, Fransisca

AU - Curtis, Louis T.

AU - Hamed, Ahmed R.

AU - Zhang, Carolyn

AU - Chau, Eric

AU - Sieving, Devon

AU - Godin, Biana

AU - Frieboes, Hermann B.

PY - 2020/5/1

Y1 - 2020/5/1

N2 - 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.

AB - 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.

KW - Breast cancer liver metastases

KW - Cancer immunotherapy

KW - Macrophage polarization

KW - Mathematical modeling

KW - Nanotherapy

KW - computational simulation

UR - http://www.scopus.com/inward/record.url?scp=85079468398&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85079468398&partnerID=8YFLogxK

U2 - 10.1007/s00262-020-02504-z

DO - 10.1007/s00262-020-02504-z

M3 - Article

VL - 69

SP - 731

EP - 744

JO - Cancer Immunology, Immunotherapy

T2 - Cancer Immunology, Immunotherapy

JF - Cancer Immunology, Immunotherapy

SN - 0340-7004

IS - 5

ER -

ID: 58736276