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

Feb 10, 2020Cancer immunology, immunotherapy : CII

Nonlinear effects of cancer nanotherapy linked to immune cell interactions shown by mathematical models and tested in mice with modified immune cells

AI simplified

Circadian Biology on OpenScience ↗PubMed ↗DOI ↗

Abstract

A mathematical model suggests that an all-M1 macrophage population may be less effective than a combination of M1 and M2 in enhancing chemotherapy response.

Tumor-associated macrophages (TAMs) can exhibit either pro-inflammatory (M1) or growth-supporting (M2) characteristics.
Modulating the macrophage phenotype is explored as a strategy to improve tumor regression in breast cancer liver metastases (BCLM).
Nanotherapy with mesoporous particles loaded with albumin-bound paclitaxel promotes M1 polarization in TAMs.
Simulation results indicate that the response to chemotherapy is not linearly dependent on the M1:M2 ratio.
Experimental findings support the hypothesis that maintaining a balance of both M1 and M2 phenotypes may enhance treatment efficacy.

AI simplified

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.

Full Text

Full text is available at the source.

View full text (PDF) ↗View full text (HTML) ↗

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

Full Text

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the circadian biology brief

Abstract

Full Text

Related papers

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the circadian biology brief