MCP-1/CCR2 axis inhibition sensitizes the brain microenvironment against melanoma brain metastasis progression
Sabina Pozzi, … , Helena F. Florindo, Ronit Satchi-Fainaro
Sabina Pozzi, … , Helena F. Florindo, Ronit Satchi-Fainaro
Published August 18, 2022
Citation Information: JCI Insight. 2022;7(17):e154804. https://doi.org/10.1172/jci.insight.154804.
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Research Article Oncology Therapeutics

MCP-1/CCR2 axis inhibition sensitizes the brain microenvironment against melanoma brain metastasis progression

Abstract

Development of resistance to chemo- and immunotherapies often occurs following treatment of melanoma brain metastasis (MBM). The brain microenvironment (BME), particularly astrocytes, cooperate toward MBM progression by upregulating secreted factors, among which we found that monocyte chemoattractant protein-1 (MCP-1) and its receptors, CCR2 and CCR4, were overexpressed in MBM compared with primary lesions. Among other sources of MCP-1 in the brain, we show that melanoma cells altered astrocyte secretome and evoked MCP-1 expression and secretion, which in turn induced CCR2 expression in melanoma cells, enhancing in vitro tumorigenic properties, such as proliferation, migration, and invasion of melanoma cells. In vivo pharmacological blockade of MCP-1 or molecular knockout of CCR2/CCR4 increased the infiltration of cytotoxic CD8+ T cells and attenuated the immunosuppressive phenotype of the BME as shown by decreased infiltration of Tregs and tumor-associated macrophages/microglia in several models of intracranially injected MBM. These in vivo strategies led to decreased MBM outgrowth and prolonged the overall survival of the mice. Our findings highlight the therapeutic potential of inhibiting interactions between BME and melanoma cells for the treatment of this disease.

Authors

Sabina Pozzi, Anna Scomparin, Dikla Ben-Shushan, Eilam Yeini, Paula Ofek, Alessio D. Nahmad, Shelly Soffer, Ariel Ionescu, Antonella Ruggiero, Adi Barzel, Henry Brem, Thomas M. Hyde, Iris Barshack, Sanju Sinha, Eytan Ruppin, Tomer Weiss, Asaf Madi, Eran Perlson, Inna Slutsky, Helena F. Florindo, Ronit Satchi-Fainaro

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Figure 3

MCP-1 inhibition delays B16-F10 MBM progression.

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MCP-1 inhibition delays B16-F10 MBM progression. (A) B16-F10 melanoma ce...
(A) B16-F10 melanoma cells were intracranially (i.cr.) inoculated in immunocompetent C57BL/6 mice to generate brain metastasis (n = 20). Three days after tumor cell inoculation into the brain, mice were treated with 100 mg/kg i.v. bindarit (n = 10) or PBS (n = 10) QOD until day 15. Image created with BioRender.com. (B) Tumor size in MRI scans at day 13. Representative images of mice bearing brain tumors in PBS- or bindarit-treated groups (n = 10); H&E staining for tumor morphology and size. Scale bar — 400 μm. Quantification of tumor size in B16-F10 brain tumor. Mean ± SD (n = 3 PBS; n = 5 bindarit). Nonparametric Student’s t test. (C) Kaplan-Meier survival curve (n = 7). Two-tailed P values from log-rank (Mantel–Cox). (D) Mouse body weight change was monitored twice a week upon injection of B16-F10 melanoma cells. Mean ± SEM of n = 10 per group. (E) Brain cryosections at day 13 (n = 3) were stained for MCP-1 (red), GFAP (activated astrocytes — green), Iba1 (activated microglia/macrophages — green), IL-6 (green), F4/80 (macrophages — green), CD31 (blood vasculature — green), PD-1/PD-L1 (exhausted T cells/inhibitory molecule — red/green), and CD8+ (cytotoxic T cells — green) markers. Nuclei are shown by DAPI staining (blue). Scale bar — 100 μm. Mean ± SEM of n = 7–10 fields per marker in n = 3 mice per group. Nonparametric Student’s t test. PD-1/PD-L1, programmed cell death 1/programmed cell death ligand 1; T, tumor.