Oral Presentation 35th Lorne Cancer Conference 2023

Spatial analysis of the metastatic brain tumor immune and extracellular matrix microenvironment (#18)

Marija Dinevska 1 , Samuel S Widodo 1 , Lucero Cuzcano 2 , Michael Papanicolaou 3 4 , Thomas R Cox 3 5 , Stanley S Stylli 1 6 , Theo Mantamadiotis 1 2 7
  1. Department of Surgery (RMH), The University of Melbourne, Melbourne, VIC, Australia
  2. Department of Microbiology and Immunology, The University of Melbourne, Melbourne, VIC, Australia
  3. Cancer Ecosystems Program, The Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW, Australia
  4. School of Life Sciences, University of Technology Sydney, Sydney, NSW, Australia
  5. School of Clinical Medicine, University of New South Wales St Vincent’s Healthcare Clinical Campus, Sydney, UNSW, Australia
  6. Department of Neurosurgery, The University of Melbourne, Parkville, VIC, Australia
  7. The Centre for Stem Cell Systems, The University of Melbourne, Melbourne, VIC, Australia

Metastatic cancer is responsible for the overwhelming majority of cancer-related deaths, and are the most common neoplasms affecting the central nervous system. Multiple components of the tumour microenvironment regulate tumour biology. However, little is known about the cellular and non-cellular composition of metastatic brain tumors and how tumor cell ontogeny influences the composition of the metastatic brain tumor microenvironment (TME). By integrating multiplex immunohistochemistry, histopathological staining, and spatial analysis of metastatic brain tumour tissue, we investigated the composition and the spatial relationship between neoplastic cells, immune cells, and the extracellular matrix (ECM). Metastatic brain tumors exhibit differences in ECM deposition compared to the most common primary brain cancer, glioblastoma, including differences in collagen fibre density. Infiltrating macrophages and T-cells are the most common immune cells in metastatic brain tumors, with an enrichment of these cells within ECM-rich regions. The dominant macrophage subtype in metastatic brain tumors are immunosuppressive/anti-inflammatory macrophages, which preferentially localize to these ECM-rich regions. Overall, our data shows that macrophages and T-cells are restricted within ECM-dense regions, which may prevent these cells from interacting with, and effectively killing neoplastic cells. We also identify tumor infiltrating macrophages as the likely key immune cells involved in establishing an immunosuppressive TME. The findings support the view that optimal therapy for patients with metastatic brain cancer would include drugs which modify the ECM, and drugs which target immunosuppressive macrophages, in addition to cytotoxic therapies.