Significance was determined using unpaired test, ****mice at 11 weeks based on MEMRI and immune profiled by circulation cytometry (Fig
Significance was determined using unpaired test, ****mice at 11 weeks based on MEMRI and immune profiled by circulation cytometry (Fig. 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. Introduction Medulloblastoma (MB) is usually a highly aggressive, WHO-grade IV embryonal tumor most commonly seen in children under 16 years of age 18, 25. Current treatments, including surgery, radiation and chemotherapy yield five-year survival rates of ~70% 25. However, survivors suffer from treatment-related neurocognitive and neuroendocrine sequelae 38. Thus, less harmful therapeutic options are urgently needed. MB is usually divided into four major subgroups (WNT, Sonic Hedgehog [SHH], Group 3 and Group 4) 45. Genomic, epigenomic, transcriptomic and proteomic analysis of tumor samples combined with clinical data have further subdivide each subgroup into subtypes, emphasizing the heterogeneity of the disease and the importance of incorporating the subtypes into clinical risk stratification 1, 5, 31. Despite the large volume of data around the intrinsic cellular drivers of MB, the potential roles of the immune microenvironment in promoting or inhibiting human MB progression have not been extensively resolved. Previous transcriptomic studies and immunohistochemical analysis of MB patient samples and mouse MB models revealed a higher level SB 239063 of immune cells in the SHH-subgroup compared to SB 239063 the other three MB subgroups, with tumor-associated macrophages/microglia (TAMs) being the major immune component 4, 22, 24, 33. TAMs, which can include both bone marrow-derived macrophages and brain-resident microglia, are considered a major contributor to immunosuppression through secretion of cytokines and inhibition of T cell functions and can thus promote cancer progression 20, 36, 50. Indeed, in studies of mouse models of glioblastoma (GBM), inhibition of colony-stimulating factor 1 receptor (CSF1R), a survival factor for normal macrophages/microglia, was found to reduce tumor progression, despite TAMs not being depleted 34, 35. A recent study showed that TAMs, and likely microglia-derived TAMs, promote SHH-MB initiation at postnatal day (P) 35 by secreting insulin-like growth factor 1 (IGF1) SB 239063 51. In contrast, another study found that knocking out tumors 33, whereas another study showed that inhibition STMY of TGF signaling in T cells, which boosts T cell killing activity, continuous mouse survival in the model 9. Therefore, further research around the immune microenvironment of different SHH-MB models is critical to explore the potential use of immunotherapy on SHH-MB patients. To investigate the role of immune cells in SHH-MB, we manipulated three different immune cell populations in an immunocompetent mouse model of sporadic SHH-MBs in which ~50% of mice pass away of disease. We discovered that tumors that progress to cancer have greater infiltration by TAMs. Furthermore, genetic removal of mature B and T cells does not alter survival in our mouse model of SHH-MB. In contrast, CSF1R inhibition prolongs mouse survival, reduces tumor size by four weeks of treatment and diminishes the infiltration of a subset of TAMs and increases the percentage of in CD8 T cells in tumors. Our studies thus reveal a critical function of TAMs in promoting tumor progression in a mouse model of SHH-MB and suggest a translational potential for CSF1R inhibition in a subset of SHH-MB patients. Results Tumors that Progress to SHH-MB have Comparable Transcriptional Profiles to Tumors that Regress To study SHH-MB SB 239063 progression, we used an immunocompetent mouse model of sporadic SHH-MB in which the human oncogenic form of the SHH receptor Smoothened (SmoM2) is usually fused to SB 239063 YFP and expressed in rare granule cell progenitors (GCPs), the main cell of origin of SHH-MBs, starting at P2 by injection of a low dose of Tamoxifen (Tm) into mice (mice revealed that only a subset of mice died from advanced tumors starting at 8 weeks (52% or 68% depending on the low dose of Tm used) (Sup.