Poster Presentation 36th Lorne Cancer Conference 2024

Spatial architecture of high-grade glioma reveals tumour heterogeneity within distinct domains  (#226)

Joel JD Moffet 1 2 , Oluwaseun E Fatunla 1 2 , Lutz Freytag 1 , Jurgen Kriel 1 2 , Jordan J Jones 3 , Samuel J Roberts-Thomson 4 , Anna Pavenko 5 , David K Scoville 5 , Liang Zhang 5 , Yan Liang 5 , Andrew P Morokoff 3 , Jim R Whittle 1 2 6 , Saskia Freytag 1 2 , Sarah A Best 1 2
  1. Personalised Oncology Division, WEHI, Melbourne, Victoria, Australia
  2. Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia
  3. Department of Surgery, Royal Melbourne Hospital, Melbourne, Victoria, Australia
  4. Department of Anatomical Pathology, Royal Melbourne Hospital, Melbourne, Victoria, Australia
  5. NanoString Technologies Inc., Seattle, Washington, USA
  6. Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

High-grade gliomas (HGG) are aggressive primary brain cancers with poor response to standard regimens, driven by immense heterogeneity. In isocitrate dehydrogenase (IDH) wild-type high-grade glioma (glioblastoma, GBM), increased intra-tumoral heterogeneity is associated with more aggressive disease. Spatial technologies can dissect complex heterogeneity within the tumour ecosystem by preserving cellular organisation in situ. We previously employed GeoMx digital spatial profiling, CosMx spatial molecular imagingand Visium spatial gene expression in experimental and validation patient cohorts to interrogate the transcriptional landscape in HGGReconstructing the tumour architecture revealed two distinct niches, one composed of tumour cells that most closely resemble normal glial cells, associated with microglia; and the other niche populated by monocytes and mesenchymal tumour cellsHowever, all these technologies are limited to confined regions of analysis, preventing comprehensive profiling across the entirety of a sample. Here, we employed Xenium in situ mapping to construct a high-resolution molecular map of heterogeneity across an entire GBM sample cross-section, permitting whole-slide investigation of the cellular communities that compose high-grade gliomaWe uncovered striking diversity in the tumour landscape and degree of spatial heterogeneity within the cellular composition of the tumour, identifying intricate vascular structures featuring T-cell infiltration. Characterisation of spatial neighbourhoods provided further validation of the distinct niches identified by our previous analysis on spatial technologies. Cell-type location and neighbourhood correspondence to the distribution of ligand-receptor expression can help determine the cells and genes contributing to distinct tumour profiles within the same sample in close proximity. This primary study reveals high levels of intra-tumoral heterogeneity in high-grade gliomas, associated with a diverse immune landscape within spatially localised regionslikely impacting response to immunotherapy treatments