TY - JOUR
T1 - MCP-1/CCR2 axis inhibition sensitizes the brain microenvironment against melanoma brain metastasis progression
AU - Pozzi, Sabina
AU - Scomparin, Anna
AU - Ben-Shushan, Dikla
AU - Yeini, Eilam
AU - Ofek, Paula
AU - Nahmad, Alessio D.
AU - Soffer, Shelly
AU - Ionescu, Ariel
AU - Ruggiero, Antonella
AU - Barzel, Adi
AU - Brem, Henry
AU - Hyde, Thomas M.
AU - Barshack, Iris
AU - Sinha, Sanju
AU - Ruppin, Eytan
AU - Weiss, Tomer
AU - Madi, Asaf
AU - Perlson, Eran
AU - Slutsky, Inna
AU - Florindo, Helena F.
AU - Satchi-Fainaro, Ronit
N1 - Publisher Copyright:
© 2022, Pozzi et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.
PY - 2022/9/8
Y1 - 2022/9/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85137666424&partnerID=8YFLogxK
U2 - 10.1172/jci.insight.154804
DO - 10.1172/jci.insight.154804
M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???
C2 - 35980743
AN - SCOPUS:85137666424
SN - 2379-3708
VL - 7
JO - JCI insight
JF - JCI insight
IS - 17
M1 - e154804
ER -
