Loss of SOCS3 in myeloid cells prolongs survival in a syngeneic model of glioma

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.

JAK/STAT inhibition in macrophages promotes therapeutic resistance by inducing expression of protumorigenic factors

“…Furthermore, Deng et al (21) reported the development of spontaneous colon tumors in the Csf1r-iCre model, suggesting that STAT3 deletion in myeloid cells enhances tumorigenesis, which is consistent with our findings in the mammary tumor models. Additionally, LysM-Cre-mediated deletion of SOCS3, a negative regulator of STAT3 activity, led to increased STAT3 activation in macrophages, reduced tumor growth, and increased survival in a mouse model of glioma (62). Finally, studies of myeloid STAT3 in the context of viral infection have demonstrated impaired activation of T cells and NK cells (63), suggesting that STAT3 regulation of myeloid cells is highly context-dependent.…”

SOCS molecules: the growing players in macrophage polarization and function

“…SOCS3 protein is commonly known to serve as a negative regulator of STAT3, which is the key physiological regulator in immune homeostasis and diseases pathogenesis [ 89 – 91 ]. SOCS3 has been shown to be induced by a wide variety of the cytokines and growth factors, such as IL-1β, 2, 4 and M-CSF [ 92 , 93 ].…”

M1 and M2 Myeloid Cells in Inflammation

“…In this model, decreased infiltration of gliomas by M2 polarized macrophages occurred. This loss of SOCS3 in myeloid cells was associated with an increased infiltration of the tumors by M1 macrophages and CD8+cytotoxic T cells with a concomitant decrease in infiltrating Treg cells [9]. This same group had previously shown that SOCS3 deficiency enhanced M1 polarization and inflammation and conversely, that Polarized myeloid cell phenotypes and associated SOCS1-SOCS3 proteins play key roles in inflammation as well as in immune regulation.…”