Human glioblastoma tumors are aggressive hard-to-treat brain cancers that have a high unmet need for new treatment options. A team of researchers led by Prof. Kiavash Movahedi and Prof. Jo Van Ginderachter (VIB-VUB), in collaboration with colleagues from VIB, VUB, and KU Leuven, have mapped the immune landscape in these glioblastoma tumors. Their results provide insights into the multifaceted role of glioblastoma-associated macrophages. This important class of immune cells infiltrates the tumors and promotes disease progression. As macrophages form an important therapeutic target for glioblastoma, the new findings provide a basis for developing new immunotherapeutic approaches for this disease. The findings were published s.
Prof. Kiavash Movahedi (VIB-VUB): "Macrophages are the next frontier in cancer immunotherapy. They can either promote or block tumor growth. In glioblastoma, these cells are present in high numbers and unfortunately stimulate tumor growth. Our intent is to find a molecular switch that pushes them in the right direction by turning them into toxic cells that attack the tumor."
The hurdles of glioblastoma immunotherapy
Immunotherapy has revolutionized cancer treatment. It has saved the lives of many patients that until recently were untreatable. However, some tumor types remain largely refractory to this therapy. This includes glioblastoma, a highly malignant primary brain tumor that is notoriously difficult to treat.
The glioblastoma tumor microenvironment, consisting out of cancer cells and infiltrating immune cells, is thought to be highly immunosuppressive and therefore impairs immune-mediated killing of cancer cells. Macrophages are important components of this microenvironment. These immune cells are co-opted to promote tumor progression and impair the efficacy of immunotherapy.
Prof. Kiavash Movahedi (VIB-VUB) explains: “A better understanding of macrophages is imperative for breaking the immunosuppressive circuits that maintain glioblastoma therapy resistance.’
Single Cell technology to map the immune landscape of the tumor
The team joined forces with the groups of Prof. Diether Lambrechts (VIB-KU Leuven), Prof. Frederik De Smet (KU Leuven), and Prof. Bart Neyns (UZ Brussel) and made use of single-cell multi-omic technologies to measure the gene and protein expression of thousands of individual immune cells that infiltrate glioblastoma tumors.
Prof. Jo Van Ginderachter (VIB-VUB): “To understand how the tumor microenvironment adapts to therapy, we analyzed tumors at different stages of the disease: following initial diagnosis before drug treatment, but also following tumor recurrence. The latter patients had previously received radioand chemotherapy, but the tumor had regrown and became therapy-resistant.’
The researchers showed that macrophages in glioblastoma tumors come in different flavors and exhibit a spectrum of activation states. Each of these macrophage subtypes may differentially affect tumor growth. Furthermore, the results indicate that the origin of tumor macrophages in part dictates how they adapt to the tumor microenvironment and that this is dependent on the disease stage.
Prof. Jo Van Ginderachter (VIB-VUB): "The detailed insight in the complexity of the macrophage compartment in tumors is thrilling. It will be exciting to discover how different types of macrophages exactly act within glioblastoma tumors and how we can translate this knowledge into directed therapies."
Testing the preclinical models
It is important to assess whether the preclinical mouse models that are used for initial drug testing accurately mimic the human disease. Therefore, the researchers also analyzed the immune cells in glioblastoma tumors from mice.
Prof. Kiavash Movahedi (VIB-VUB): “The tumor macrophages in humans and mice showed a high degree of conservation. This indicates that mouse models are useful to further delineate the role and therapeutic potential of these cells.’