Physical Poster + E-Poster Presentation 34th Lorne Cancer Conference 2022

Tissue remodelling shapes the tumour immune microenvironment in glioma and GBM (#251)

Samuel Widodo 1 , Marija Dinevska 1 , Liam Furst 2 , Lucero Cuzcano 2 , Yitong Fang 2 , Stefano Mangiola 3 , Paul Neeson 4 , Phil Darcy 4 , Rob Ramsay 4 , Fabienne MacKay 1 , Stanley Stylli 1 5 , Theo Mantamadiotis 1 2 6
  1. Department of Surgery (RMH), The University of Melbourne, Melbourne, VIC, Australia
  2. Department of Microbiology and Immunology, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
  3. Bioinformatics Division, The Walter and Eliza Hall Institute, Parkville, VIC, Australia
  4. Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
  5. Department of Neurosurgery, Royal Melbourne Hospital, Parkville, VIC, Australia
  6. The Centre for Stem Cell Systems, The University of Melbourne, Melbourne, VIC, Australia

Glioblastoma (GBM) is an incurable brain cancer, with a 5-year survival rate of less than 5%. Although tissue remodelling has been studied in some cancers, nothing is known about tissue remodelling during brain tumour development. There is an emerging view that tumours resemble chronic wounds, which fail to heal. Transcriptomic data reveals that extra-cellular matrix (ECM) protein mRNAs in GBM, including the most abundant ECM protein, collagen, is pro-oncogenic. Collagen influences tumour immune cell infiltration, T-cell exhaustion, and resistance to immune checkpoint inhibition. It has also been demonstrated that tumour-associated macrophages regulate collagen deposition by stimulating collagen-secreting cells via TGF-β signalling. However, the ECM-immune cell relationship in brain cancer oncogenesis remains unexplored.

To investigate the ECM-immune cell relationship in brain cancer, we performed multiplex immunohistochemistry on over 150 patient glioma samples, representing different tumour grades, using immune cell biomarkers. The  tumour tissue samples were also stained using Masson’s Trichrome staining, which enabled identification of ECM-rich and tumour-rich regions. Spatial analysis was also performed to identify immune cell distribution in the ECM-rich and tumour-rich regions. 

Our results showed high infiltration of myeloid cells in both low-grade and high-grade gliomas, whereas T-cell infiltration increased with disease progression. The proportion of activated immune cells also correlated with tumour grade. The data demonstrated an increase of ECM deposition in GBM, in comparison to lower-grade glioma. An accumulation of immunosuppressive macrophages and T-cells in perivascular collagen-rich regions in GBM was also observed, suggesting a relationship between infiltrating immune cells and the ECM. Furthermore, in patients over 40 years old, GBM tissue from male patients exhibited higher ECM deposition, compared to females. 

Future research will include identifying ECM protein-producing cells in GBM and investigating their relationships with immune cells and tumour cells to reveal a new therapeutical strategy.