Abstract
In glioma, microglia and macrophages are the largest population of tumor-infiltrating cells, referred to as glioma associated macrophages (GAMs). Herein, we sought to determine the role of Suppressor of Cytokine Signaling 3 (SOCS3), a negative regulator of Signal Transducer and Activator of Transcription 3 (STAT3), in GAM functionality in glioma. We utilized a conditional model in which SOCS3 deletion is restricted to the myeloid cell population. We found that SOCS3-deficient bone marrow-derived macrophages display enhanced and prolonged expression of pro-inflammatory M1 cytokines when exposed to glioma tumor cell conditioned medium in vitro. Moreover, we found that deletion of SOCS3 in the myeloid cell population delays intracranial tumor growth and increases survival of mice bearing orthotopic glioma tumors in vivo. Although intracranial tumors from mice with SOCS3-deficient myeloid cells appear histologically similar to control mice, we observed that loss of SOCS3 in myeloid cells results in decreased M2 polarized macrophage infiltration in the tumors. Furthermore, loss of SOCS3 in myeloid cells results in increased CD8+ T-cell and decreased regulatory T-cell infiltration in the tumors. These findings demonstrate a beneficial effect of M1 polarized macrophages on suppressing glioma tumor growth, and highlight the importance of immune cells in the tumor microenvironment.
Highlights
On a cellular level, glioblastoma (GBM) tumors are extremely heterogeneous, consisting of resident tumor cells, tumor initiating cells, infiltrating immune cells, endothelial cells and other tumor associated stromal cells, which makes developing targeted therapies a challenge [1]
We have previously shown that macrophages deficient in Suppressor of Cytokine Signaling 3 (SOCS3) display prolonged STAT1/Signal Transducer and Activator of Transcription 3 (STAT3) activation and increased M1 gene expression in response to LPS, IL-6 and IFN-γ stimulation [14]
STAT1 phosphorylation was enhanced in SOCS3−/− macrophages when exposed to GL261 conditioned medium (GCM); total levels of STAT1 protein were enhanced, and densitometric quantification reveals no elevated STAT1 activation in Suppressor Of Cytokine Signaling (SOCS)−/− macrophages compared to SOCS3fl/fl cells (Supplementary Figure 1)
Summary
Glioblastoma (GBM) tumors are extremely heterogeneous, consisting of resident tumor cells, tumor initiating cells, infiltrating immune cells, endothelial cells and other tumor associated stromal cells, which makes developing targeted therapies a challenge [1]. Microglia are the resident tissue macrophage of the brain, macrophages are recruited to the tumor from peripheral hematopoietic stem cell compartments. While these two cell populations (microglia and macrophages) originate from different sites, they exhibit similar functions in GBM. M1 macrophages secrete pro-inflammatory cytokines, including TNF-α, IL-6 and CXCL10, present antigen to immune cells and phagocytize tumor cells. M2 macrophages secrete immune-suppressive cytokines such as IL-10 and TGF-β, promote T regulatory (Treg) cell differentiation and aid in tumor progression. These represent two extreme examples of M1/M2 polarization. It has generally been accepted that upon arrival at the tumor site, macrophages become polarized to an anti-inflammatory www.impactjournals.com/oncotarget
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
