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Dang, Mai T.; Gonzalez, Michael V.; Gaonkar, Krutika S.; Rathi, Komal S.; Young, Patricia; Arif, Sherjeel; Zhai, Li; Alam, Zahidul; Devalaraja, Samir; To, Tsun Ki Jerrick; Folkert, Ian W.; Raman, Pichai; Rokita, Jo Lynne; Martinez, Daniel; Taroni, Jaclyn N.; Shapiro, Joshua A.; Greene, Casey S.; Savonen, Candace; Mafra, Fernanda; Hakonarson, Hakon; Curran, Tom; Haldar, Malay
Cell reports (Cambridge), 03/2021, Letnik: 34, Številka: 13Journal Article
Tumor-associated macrophages (TAMs) play an important role in tumor immunity and comprise of subsets that have distinct phenotype, function, and ontology. Transcriptomic analyses of human medulloblastoma, the most common malignant pediatric brain cancer, showed that medulloblastomas (MBs) with activated sonic hedgehog signaling (SHH-MB) have significantly more TAMs than other MB subtypes. Therefore, we examined MB-associated TAMs by single-cell RNA sequencing of autochthonous murine SHH-MB at steady state and under two distinct treatment modalities: molecular-targeted inhibitor and radiation. Our analyses reveal significant TAM heterogeneity, identify markers of ontologically distinct TAM subsets, and show the impact of brain microenvironment on the differentiation of tumor-infiltrating monocytes. TAM composition undergoes dramatic changes with treatment and differs significantly between molecular-targeted and radiation therapy. We identify an immunosuppressive monocyte-derived TAM subset that emerges with radiation therapy and demonstrate its role in regulating T cell and neutrophil infiltration in MB. Display omitted •Sonic Hedgehog (SHH) subgroup of medulloblastoma (MB) recruits diverse macrophages•Radiation or molecular-targeted therapy alters macrophage distribution in SHH-MB•Radiation recruits immunosuppressive monocyte-derived macrophages (TAMoMacs) in SHH-MB•Radiation-induced TAMoMacs regulate CD8 T cell and neutrophil numbers in SHH-MB Dang et al. show that the sonic hedgehog subgroup of medulloblastoma (SHH-MB) contains macrophages derived from microglia and circulating monocytes. Radiation therapy, but not treatment targeting the SHH pathway, led to recruitment of immunosuppressive monocyte-derived macrophages that reduced T cells and neutrophils in the tumor microenvironment.
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