Glioblastoma tumours build a molecular scaffold around themselves that disarms the body’s immune defences, and this project will map exactly how that scaffold works. The problem is that immunotherapies—drugs that help the immune system attack cancer—work well against many cancers but fail against glioblastoma, the most common and aggressive adult brain cancer. Evidence points to two types of immune cells, myeloid-derived suppressor cells and tumour-associated macrophages, which the tumour recruits to shut down cancer-killing immune responses. What remains unknown is how the tumour’s extracellular matrix—the complex mesh of molecules surrounding it—drives those cells into their suppressive state. This project will use patient tumour samples and a high-resolution imaging technique called 3D-OrbiSIMS to link specific matrix patterns with immune cell behaviour. The researchers will then test whether drugs that alter the matrix can restore normal immune function in the lab. If successful, this fundamental science could reveal new drug targets for glioblastoma. Because the work uses only human cells, any targets identified would be directly relevant to patients, potentially opening a route to treatments where current immunotherapies have failed.
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Context Glioblastoma is the most common and aggressive brain cancer in adults. Despite decades of research even the best treatments currently available provide limited benefits to patients with this disease. New treatments that help the body’s immune system fight cancer (‘immunotherapy’) have worked well in other cancers, but unfortunately not in glioblastoma. It is thought that a key reason for glioblastoma’s resistance to immunotherapy is that the tumour generates an environment that suppresses cytotoxic (cancer-killing) immune responses. This prevents immune cells from attacking cancer cells, making immunotherapy ineffective. Research suggests two immune cell types, myeloid-derived suppressor cells (MDSC) and tumour-associated macrophages (TAM), are recruited by glioblastoma to suppress anti-cancer immunity. Understanding how this is controlled should allow us to devise new treatments. The tumour environment is surrounded by a complex molecular scaffold called the extracellular matrix (ECM), which is a major component of glioblastoma [1]. ECM influences immunity, interfering with normal immune responses and promoting resistance to treatment [2]. My project investigates the relationship between glioblastoma ECM and suppressive MDSC and TAM to find new potential treatment targets. Challenge the project addresses MDSC/TAM and ECM are thought to support tumour growth. However, the impact of ECM on TAM/MDSC and the way ECM and immune cells shape glioblastoma’s tumour environment are not fully understood. Furthermore, whether ECM and TAM/MDSC can be targeted to help patients with glioblastoma remains unclear. I believe that understanding the role of ECM and TAM/MDSC in brain tumours could pave the way for new treatments for glioblastoma. Aims and objectives This project aims to define the effect of ECM on TAM and MDSC in glioblastoma by addressing the following objectives: Determine the relationship between ECM, TAM/MDSC, and survival. Identify mechanisms by which glioblastoma ECM influences immune cells. Test if altering the tumour’s ECM can restore cancer-fighting immune responses. A key feature of my work is exclusive use of glioblastoma patients’ cells in experiments to confirm if specific ECM patterns drive the emergence of immunosuppressive MDSC/TAM. Methods Aim 1: The molecular structure and composition of glioblastoma ECM will be determined by taking high-resolution pictures of tumour specimens with an innovative technology called 3D-OrbiSIMS. These same specimens will next be stained to determine the location of subsets of immune cells. These two sets of data will be brought together to understand how the pattern of ECM molecules relates to immune cells in the tumour. Aim 2: Glioblastoma cells obtained during surgery or ECM produced by these cells will be cultured in the laboratory with healthy immune cells. This will allow us to better understand aspects of glioblastoma and ECM that drive normal immune cells to become MDSC/TAM. Aim 3: The ECM pattern of glioblastoma cells will be changed with specific drugs before adding immune cells. Drugs will be selected to reflect changes in ECM identified in previous experiments. Potential applications/benefits Data obtained from this project will help identify ways in which ECM and TAM/MDSC can be targeted to boost anti-tumour immune responses, which may lead to new treatments for patients with glioblastoma. Wei https://doi.org/10.1186/s12885-024-12751-3 Popova https://doi.org/10.3390/cancers14010238
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