CSF1R inhibition depletes tumor-associated macrophages and attenuates tumor progression in a mouse sonic Hedgehog-Medulloblastoma model
| Autor: | Andrey Korshunov, Alexandra L. Joyner, Reeti Mayur Sanghrajka, Antoine Tanne, Juan J. Lafaille, N. Sumru Bayin, Raquel Duque Nascimento Arifa, Veronika Kana, Zhimin Lao, Harikrishna Rallapalli, Nina Bhardwaj, Alexandre Wojcinski, Daniel H. Turnbull, Miriam Merad, I-Li Tan |
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| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine Cancer Research Apoptosis Context (language use) Biology Article Mice 03 medical and health sciences 0302 clinical medicine Immune system Tumor-Associated Macrophages Basic Helix-Loop-Helix Transcription Factors Tumor Cells Cultured Tumor Microenvironment Genetics medicine Animals Humans Cytotoxic T cell Hedgehog Proteins Sonic hedgehog Cerebellar Neoplasms Molecular Biology Cell Proliferation Mice Knockout Medulloblastoma Tumor microenvironment Microglia Prognosis medicine.disease Mice Inbred C57BL Disease Models Animal 030104 developmental biology medicine.anatomical_structure Receptors Granulocyte-Macrophage Colony-Stimulating Factor Tumor progression 030220 oncology & carcinogenesis Cancer research biology.protein Female |
| Zdroj: | Oncogene |
| ISSN: | 1476-5594 0950-9232 |
| Popis: | 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 four 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. |
| Databáze: | OpenAIRE |
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