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

Abstract

<b>Purpose:</b> While the tumor microenvironment has been known to play an integral role in tumor progression, the function of nonresident bone marrow-derived cells (BMDC) remains to be determined in neurologic tumors. Here we identified the contribution of BMDC recruitment in mediating malignant transformation from low- to high-grade gliomas.<b>Experimental Design:</b> 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).<b>Results:</b> 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.<b>Conclusions:</b> We demonstrate that impaired recruitment of CD11b⁺ myeloid cells with a JAK1/2 inhibitor inhibits glioma progression <i>in vivo</i> and prolongs survival in a murine glioma model. <i>Clin Cancer Res; 23(12); 3109-19. ©2016 AACR</i>.