Circulating immune profiling reveals impaired monocyte phenotypes and trajectories driving immunosuppression in glioblastoma
Description
Glioblastoma (GBM) is a highly aggressive and lethal brain tumour that induces profound local and systemic immune suppression. These immune alterations are reflected in the circulation contributing to disease progression and poor immunotherapy outcomes. However, the diagnostic and therapy predictive potential of monitoring peripheral alterations are still an unexplored medical area in GBM. To dissect the underlying mechanisms with clinical translational value, we combined mass cytometry and single-cell RNA-sequencing of peripheral blood mononuclear cells from GBM patients, alongside targeted flow cytometry and systematic analyses of patient-derived datasets. Relative to healthy donors, circulating immune cells in GBM patients displayed marked alterations within the myeloid compartment, including accumulation of myeloid-derived suppressor cells (MDSCs) and reduction of non-classical monocytes, alongside with decreased proportions of CD4+ T and NK/NKT cells. Distinct monocyte subsets exhibited specific modulatory traits and were distributed across defined circulating differentiation trajectories, with MDSC-like populations occupying intermediate states. Trajectory patterns were highly consistent between cytometry and RNA-sequencing analyses. Among these subsets, monocytes with antigen-presenting cell phenotype showed a greater propensity to extravasate and differentiate into tumour-associated macrophages. Heterogeneous monocyte populations displayed discrete immune functions and shared a GBM-associated signature characterized by reduced major histocompatibility complex (MHC) class II expression and elevated levels of inflammation-limiting mediators, such as IL1R2 and CD163. Additionally, CD4+ and CD8+ T cells, NK and B cells exhibited distinct transcriptional activated profiles, mainly exemplified by up-regulation of alarmins S100A8/S100A9. Lastly, inferred cell-cell communication networks highlighted disrupted patterns that reinforced immunosuppressive traits, including prominent reduction of MHC class II - CD4 interactions. Overall, our study presents a comprehensive map of systemic immune reprogramming in GBM, highlighting alterations in leukocyte composition, identifying distinct monocytic phenotypes, mapping their regulatory networks, uncovering associations with tumour infiltration and charting their ligand-receptor interactions. These insights advance our understanding of systemic immune dysfunction and identify novel avenues for non-invasive, easily traceable peripheral biomarkers and therapeutic intervention aimed at restoring an effective anti-tumour immunity in GBM.
Files
Institutions
- Luxembourg Institute of HealthStrassen
Categories
Funders
- FNRS-TélévieGrant ID: GBodImm no. 7.8513.18/7651720F, ImmoGB 7.8505.20/7.6603.22