Children’s Hospital of Philadelphia
Medulloblastomas comprises the vast majority of pediatric embryonal tumors and by definition arise in the posterior fossa, where they constitute approximately 40% of all posterior fossa tumors. Other forms of embryonal tumors each make up 2% or less of all childhood brain tumors.The clinical feature
Macrophages in SHH Subgroup Medulloblastoma Display Dynamic Heterogeneity That Varies With Treatment Modality
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.
Mai T. Dang, Michael V. Gonzalez, Krutika S. Gaonkar, Komal S. Rathi, Patricia Young, Sherjeel Arif, Li Zhai, Zahidul Alam, Samir Devalaraja, Tsun Ki Jerrick To, Ian W. Folkert, Pichai Raman, Jo Lynne Rokita, Daniel Martinez, Jaclyn N. Taroni, Joshua A. Shapiro, Casey S. Greene, Candace Savonen, Fernanda Mafra, Hakon Hakonarson, Tom Curran, Malay Haldar