Recent advances in immuno-oncology offer promising perspectives in cancer treatment. However, some diseases such as childhood and adulhood brain tumors remain highly lethal. In steady-state, brain cell populations are composed of neurons and glial cells in approximately even proportions. Microglia is the denomination for tissue resident macrophages of the central nervous system (CNS), being the most represented immune cell population. In mice, these macrophages are migrating from the yolk sac before the emergence of BBB and self-renew directly in the brain through lifespan. These cells are known to contribute to brain development and homeostasis through regulation of glial cell survival, apoptosis, or phagocytosis but also in synapse pruning. In the last decade, huge breakthroughs in high-dimensional assays have been made – exemplified by single-cell RNA sequencing (scRNAseq), single-cell ATAC sequencing (scATACseq), high-dimensional flow cytometry and other related methods, allowing us to precisely characterize cells by accessing multi-omic information. Thus, precise characterizations of myeloid cells in brain have begun to arise. For example, border associated-macrophages (BAMs) and microglia have been shown to display distinct transcriptional signatures in steady state. In glioblastoma, Tumor Associated Macrophages (TAMs) have been proven to constitute the largest population of immune cells in TME. Those TAMs express different transcriptional identity compared to steady state microglia, exemplified by the marker TREM2 whose role isn’t completely elucidated. Intra-brain TAMs heterogeneity also exists as those latter are comprised of Tumor associated Monocyte-Derived Macrophages (MDMs) and Tumor-Associated Microglia, highlighting the potential importance of ontogeny in the immune function. This hypothesis is supported by the recent findings of Disease Induced Macrophages (DIMs) and Disease Associated Microglia (DAMs) in Alzheimer’s Disease (AD), also linked with TREM2 pathway. Deciphering molecular pathways and cell to cell communication is key in elucidating new therapeutical targets. In adult glioblastoma, tumor-associated reactive astrocytes interacting with microglia participate in immunosuppressive TME by potential reprogramming. Even if TAMs appear to perform immunosuppression in the TME, their different subtypes but also many activation states of glial cells are not properly identified. The stability and the factors imprinting and driving these cell programs are even less understood. Moreover, interactions of those cells with the immune compartment should be investigated more in depth.
Are some subsets of glial and immune cells specifically interacting? Do macrophage ontogeny and plasticity matter in those interactions? Could brain macrophages heterogeneity drive glia diversity? Which pathways play a role in these interactions? Does glial transcriptional diversity imply functional diversity?
As our lab already did in the past, we first aim to capture the transcriptomic heterogeneity by integrating human brain scRNAseq datasets from various brain tumors into a single “-Verse”. To build this “Brain Tumor (BT)-Verse”, we gathered publicly available or in-house made datasets processing brain tissues from adult, pediatric patients or mixed. Those patients were either healthy or diagnosed with brain cancer.
Thus, tumor and immune subsets could be identified with transcriptomic surface or intracellular markers along with key pathways and potential inter-populations interactions. Based on this BT-VERSE, we can study common and specific program to adult and pediatric patients and determine potential key regulators. The next step will be to perform ATAC-seq to confirm key targets, spectral cytometry to validate macrophage heterogeneity at the protein level.
