Patient-derived organoids recapitulate glioma-intrinsic immune program and progenitor populations of glioblastoma

Glioblastoma multiforme (GBM) is a highly lethal human cancer thought to originate from a self-renewing and therapeutically-resistant population of glioblastoma stem cells (GSCs). The intrinsic mechanisms enacted by GSCs during 3D tumor formation, however, remain unclear, especially in the stages prior to angiogenic/immunological infiltration. In this study, we performed a deep characterization of the genetic, immune, and metabolic profiles of GBM organoids from several patient-derived GSCs (GBMO). Despite being devoid of immune cells, transcriptomic analysis across GBMO revealed a surprising immune-like molecular program, enriched in cytokine, antigen presentation and processing, T-cell receptor inhibitors, and interferon genes. We find two important cell populations thought to drive GBM progression, Special AT-rich sequence-binding protein 2 ([SATB2.sup.+]) and homeodomain-only protein homeobox ([HOPX.sup.+]) progenitors, contribute to this immune landscape in GBMO and GBM in vivo. These progenitors, but not other cell types in GBMO, are resistant to conventional GBM therapies, temozolomide and irradiation. Our work defines a novel intrinsic immune-like landscape in GBMO driven, in part, by [SATB2.sup.+] and [HOPX.sup.+] progenitors and deepens our understanding of the intrinsic mechanisms utilized by GSCs in early GBM formation. Keywords: organoids, glioblastoma stem cells, interferon, HOPX, SATB2