Malignant Astrocytic Tumor Progression Potentiated by JAK-mediated Recruitment of Myeloid Cells

Abstract

Purpose While the tumor microenvironment has been known to play an integral role in tumor progression, the function of non-resident bone marrow-derived cells (BMDCs) remains to be determined in neurological tumors. Here we identified the contribution of BMDC recruitment in mediating malignant transformation from low- to high-grade gliomas. Experimental Design We analyzed human blood and tumor samples from patients with low- and high-grade gliomas. A spontaneous platelet derived growth factor (PDGF) murine glioma model (RCAS) was utilized to recapitulate human disease progression. Levels of CD11b+/Gr1+ BMDCs were analyzed at discrete stages of tumor progression. Using bone marrow transplantation, we determined the unique influence of BMDCs in the transition from low- to high-grade glioma. The functional role of these BMDCs was then examined using a JAK 1/2 inhibitor (AZD1480). Results CD11b+ myeloid cells were significantly increased during tumor progression in peripheral blood and tumors of glioma patients. Increases in CD11b+/Gr1+ cells were observed in murine peripheral blood, bone marrow, and tumors during low-grade to high-grade transformation. Transient blockade of CD11b+ cell expansion using a JAK 1/2 Inhibitor (AZD1480) impaired mobilization of these cells and was associated with a reduction in tumor volume, maintenance of a low-grade tumor phenotype and prolongation in survival. Conclusion We demonstrate that impaired recruitment of CD11b+ myeloid cells with a JAK1/2 inhibitor inhibits glioma progression in vivo and prolongs survival in a murine glioma model.

Tumor-associated reactive astrocytes aid the evolution of immunosuppressive environment in glioblastoma

“…In addition, we showed that tumor cell spread was significantly reduced especially if slices were pretreated by JAK inhibitor. The reduced number of reactive astrocytes by JAK inhibitor 38 , as well as reduction of tumor growth and increased recruitment of myeloid cell within the tumor was recently investigated 39 . In summary, we reported the immunomodulatory properties of tumor-associated astrocytes within the human glioblastoma environment.…”

Immune landscapes associated with different glioblastoma molecular subtypes

“…It has been proposed that they act via the expression of the transcription factor STAT3, whereby they produce cytokines to promote a tumor-supportive environment by suppressing the proliferation of anti-tumor CD4 + and CD8 + T cells and promoting the activity of regulatory CD4 + T cells [20]. Interfering with the pro-tumorigenic function of M2 macrophages has been shown to be effective in reducing glioma progression in mouse models and has been proposed as a therapeutic strategy [33, 35].…”

The Role and Therapeutic Targeting of JAK/STAT Signaling in Glioblastoma

“…Various cytokines—but particularly IL-6—are associated with the infiltration of MDSCs in the TME, which are positively correlated with glioma grade and have been shown to exert immune suppressive effects against T and NK cells through expression of enzymes such as arginase that trigger T cell arrest and apoptosis [ 112 , 113 , 114 , 115 , 116 , 117 ]. MDSCs also express IFN-α, which signals through interferon receptor type 1 (IFNAR1) to activate JAK1/STAT1 signaling, thereby upregulating expression of co-inhibitory molecule programmed death ligand-1 (PD-L1) [ 114 ].…”