Brain section from a Glioblastoma patient-derived orthotopic xenograft mouse model stained with IBA1 showing microglia/macrophage morphological heterogeneity.

Brain section from a Glioblastoma patient-derived orthotopic xenograft mouse model stained with IBA1 showing microglia/macrophage morphological heterogeneity.

Representation of single-cell RNA-sequencing data showing different tumour and stromal cells isolated from a Glioblastoma syngeneic mouse model.

Representation of single-cell RNA-sequencing data showing different tumour and stromal cells isolated from a Glioblastoma syngeneic mouse model.

In vitro phagocytosis assay of microglia/macrophages.

In vitro phagocytosis assay of microglia/macrophages.

Elucidating tumour-associated microglia/macrophage heterogeneity for personalized immunotherapy in Glioblastoma

Glioblastoma (GBM) is the most common primary brain tumour and is inevitably lethal. Given its poor response to standard treatment with surgery, radiation and chemotherapy, it is an attractive target for novel cures such as immunotherapy. Tumour-associated microglia/macrophages (TAMs), which constitute up to 30-40% of the bulk tumour mass, outnumber infiltrating lymphocytes in these tumours. This scarcity of lymphocytes in the tumour microenvironment is in contrast with other tumour types, such as melanoma or lung cancer, therefore classifying GBM into the category of “cold tumours”. Due to their large number in the tumour microenvironment, TAMs are a key target for GBM immunotherapy. Despite extensive efforts in this direction, the heterogeneity of TAMs in GBM onset and progression as well as how specific TAM subpopulations may affect current immunotherapeutic approaches, including vaccines, oncolytic viruses and immune-checkpoint inhibitors, remains unclear. Therefore, our understanding of the complexity and diversity of TAM adaptive features depending, for example, on tumour stage and landscape, is critical to develop novel personalized immune therapeutic strategies for GBM patients.

​Here we focus on the identification and functional characterization of specific TAM subpopulations in GBM. Our hypothesis is that specific microglia/macrophage subpopulations may display differential adaptive features to the tumour and may be specifically targeted according to specific stages and landscapes. Hence, we aim to acquire a functional understanding of the complex heterogeneity of TAMs by elucidating the cellular and molecular mechanisms underlying their tumour-associated immunological properties. To achieve this goal, we characterize TAMs heterogeneity in patient-derived orthotopic xenograft and syngeneic mouse models and translate our investigations to GBM patient biopsies.

Overall, we are strongly convinced that elucidating the functional diversity of the immunological hallmarks of TAMs in the tumour microenvironment, together with emerging evidences on neoplastic cells heterogeneity, will be key to the successful discovery of novel targets allowing to steer TAMs towards anti-tumour functions, for instance by enhancing their phagocytic and antigen presenting cell properties to respectively engulf tumour cells and recruit lymphocytes. We strongly believe that our findings will contribute to the development of innovative personalized immunotherapeutic strategies for GBM patients.

This project is supported by the Luxembourg National Research Fund (PRIDE15/10675146/CANBIO), the Luxembourg Institute of Health & Luxembourg Centre for Systems Biomedicine (MIGLISYS) and the Fondation du Pélican de Mie and Pierre Hippert-Faber Under the Aegis of Fondation de Luxembourg.