GSE174624
The establishment of human low-grade glioma xenografts requires CD4 T cell-mediated suppression of astrocyte Cxcl10 production
One of the major barriers to identifying improved treatments for pediatric low-grade brain tumors (gliomas) is the inability to reproducibly generate reliable human xenografts. This limitation reflects the dependency of these tumors on trophic support from non-neoplastic cells in the tumor microenvironment. In an effort to surmount this barrier, we leveraged human induced pluripotent stem cell (hiPSC) engineering to generate low-grade glioma (LGG)-like lesions in immune-compromised mice, representing the two most common pediatric LGG (pilocytic astrocytoma) molecular alterations. This platform also enabled the identification of the likely cells of origin for these tumors. In addition, we discovered a CD4+ T cell-astrocyte immune circuit in which CXCL10 was both necessary and sufficient for human hiPSC-LGG formation, enabling the successful growth of patient-derived pediatric LGGs in vivo. Taken together, these avatars establish experimental platforms to elucidate pediatric LGG pathogenesis, cellular origins, and signaling pathway dependencies relevant to future precision medicine strategies. Overall design: Examination of different transcript expression in WT or Rag1-/- mouse brainstem cells