ABSTRACT
The immune microenvironment of tumors can play a critical role in promoting or inhibiting tumor progression depending on the context. We present evidence that tumor-associated macrophages/microglia (TAMs) can promote tumor progression in the sonic hedgehog subgroup of medulloblastoma (SHH-MB). By combining longitudinal manganese-enhanced magnetic resonance imaging (MEMRI) and immune profiling of a sporadic mouse model of SHH-MB, we found the density of TAMs is higher in the ~50% of tumors that progress to lethal disease. Furthermore, reducing regulatory T cells or eliminating B and T cells in Rag1 mutants does not alter SHH-MB tumor progression. As TAMs are a dominant immune component in tumors and are normally dependent on colony-stimulating factor 1 receptor (CSF1R), we treated mice with a CSF1R inhibitor, PLX5622. Significantly, PLX5622 reduces a subset of TAMs, prolongs mouse survival, and reduces the volume of most tumors within 4 weeks of treatment. Moreover, concomitant with a reduction in TAMs the percentage of infiltrating cytotoxic T cells is increased, indicating a change in the tumor environment. Our studies in an immunocompetent preclinical mouse model demonstrate TAMs can have a functional role in promoting SHH-MB progression. Thus, CSF1R inhibition could have therapeutic potential for a subset of SHH-MB patients.
Subject(s)
Cerebellar Neoplasms/prevention & control , Disease Models, Animal , Hedgehog Proteins/physiology , Medulloblastoma/prevention & control , Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/antagonists & inhibitors , Tumor-Associated Macrophages/immunology , Animals , Apoptosis , Basic Helix-Loop-Helix Transcription Factors/physiology , Cell Proliferation , Cerebellar Neoplasms/etiology , Cerebellar Neoplasms/metabolism , Cerebellar Neoplasms/pathology , Female , Humans , Male , Medulloblastoma/etiology , Medulloblastoma/metabolism , Medulloblastoma/pathology , Mice , Mice, Inbred C57BL , Mice, Knockout , Prognosis , Tumor Cells, Cultured , Tumor MicroenvironmentABSTRACT
Both pluripotent embryonic stem cells (ESCs), established from preimplantation murine blastocysts, and epiblast stem cells (EpiSCs), established from postimplantation embryos, can self-renew in culture or differentiate into each of the primary germ layers. While the core transcription factors (TFs) OCT4, SOX2, and NANOG are expressed in both cell types, the gene expression profiles and other features suggest that ESCs and EpiSCs reflect distinct developmental maturation stages of the epiblast in vivo. Accordingly, "naïve" or "ground state" ESCs resemble cells of the inner cell mass, whereas "primed" EpiSCs resemble cells of the postimplantation egg cylinder. To gain insight into the relationship between naïve and primed pluripotent cells, and of each of these pluripotent states to that of nonpluripotent cells, we have used FAIRE-seq to generate a comparative atlas of the accessible chromatin regions within ESCs, EpiSCs, multipotent neural stem cells, and mouse embryonic fibroblasts. We find a distinction between the accessible chromatin patterns of pluripotent and somatic cells that is consistent with the highly related phenotype of ESCs and EpiSCs. However, by defining cell-specific and shared regions of open chromatin, and integrating these data with published gene expression and ChIP analyses, we also illustrate unique features of the chromatin of naïve and primed cells. Functional studies suggest that multiple stage-specific enhancers regulate ESC- or EpiSC-specific gene expression, and implicate auxiliary TFs as important modulators for stage-specific activation by the core TFs. Together these observations provide insights into the chromatin structure dynamics accompanying transitions between these pluripotent states.