14 April 2021 A new study has identified the way in which a severe form of brain cancer, glioblastoma, evades the body’s own immune response, by using signals normally found in immune cells. This work offers a new way to study immunotherapies for glioblastoma. Glioblastoma multiforme is an incurable form of brain cancer. Treatment options are limited and just a quarter of glioblastoma patients survive more than one year. One of the reasons Glioblastoma is so hard to treat is because it has many distinct types, in terms of the genetic makeup and how those genes are expressed (transcriptional profile). In one of these distinct tumour subtypes (mesenchymal glioblastoma), the tumour supresses the immune environment around the cancer cells making it harder for the body to defend itself against those invasive cells. For the first time, a team at the University of Edinburgh have identified the mechanism by which glioblastoma multiforme evades the immune system. By engineering immune-resistant glioblastomas in mice, CRM scientists have shown that the cancer cells mimic the way genes are expressed in immune cells, overcoming the natural immune response to cancerous cells. The study engineered glioblastoma mutations into brain (neural) stem cells using the CRISPR/Cas9 gene editing technique. Mice transplanted with these cells develop glioblastoma. Innovatively, the team subsequently removed some of these glioblastoma cells and transplanted them into the brain of a new mouse. This process was then repeated, taking cells from the new mouse and transplanting them into a third mouse. With each transplantation, the cells altered in response to serial immune attack, resulting in cancer cells that could evade the immune system. Professor Steven Pollard and colleagues were surprised to find that the resulting cells were not genetically different, but that there was a profound difference in which genes were switched on or off (the transcriptional profile) of those cells. Cells produce proteins according to a blueprint laid out in the genes, however which genes are switched on or off is controlled by other signals called transcription factors. The transplanted cancer cells were found to have adapted by highjacking transcription factors that are normally used by the immune system. The study found that the mouse glioblastoma is representative of the human disease, as cells from glioblastoma patients showed a similar transcriptional profile to those from the transplanted mice. The immunoedited mouse cells will provide a useful model to test immunotherapies for glioblastoma. We uncovered an unexpected arms race between the cancer cells and the immune system. Surprisingly as the tumour cells are attacked by the immune system, they have a plasticity to change the sets of genes which are turned on, and ‘hijack’ molecular processes that enable them to hide from the immune attack. The new experimental tools we’ve built should now have practical value in helping in the development of new treatments for these brain tumours that harnesses the ability of the immune system. Professor Steven Pollard This study has been published in Cell and was funded by Cancer Research UK (CRUK). Journal article in Cell Pollard research group Image Engineered glioblastoma tagged with a green fluorescent probe. Credit: Neza Alfazema This article was published on 2024-02-26
