Distinct Myeloid Derived Suppressor Cell Populations in Human Glioblastoma
The diversity of transcriptional programs and cellular plasticity of glioma-associated myeloid cells, and thus their contribution to tumor growth and immune evasion, is poorly understood. We performed single cell RNA-sequencing of immune and tumor cells from 33 glioma patients of varying tumor grades. We identified two populations characteristic of myeloid derived suppressor cells (MDSC) that were unique to IDH wild type glioblastomas (GBM) and absent in IDH mutant low-grade gliomas and IDH mutant grade IV astrocytomas: i) an early progenitor population (E-MDSC) characterized by strong upregulation of multiple catabolic, anabolic, oxidative stress, and hypoxia pathways typically observed within tumor cells themselves, and ii) a monocytic MDSC (M-MDSC) population. Spatial transcriptomics demonstrated that the E-MDSCs geographically co-localize with a subset of highly metabolic glioma stem-like tumor cells with a mesenchymal program in the pseudopalisading region, a pathognomonic feature of GBMs associated with poor prognosis. Ligand-receptor interaction analysis revealed symbiotic cross-talk between the stem-like tumor cells and E-MDSCs in GBM, whereby glioma stem cells produce specific chemokines attracting E-MDSCs, which in turn produce growth and survival factors for the tumor cells; in particular the FGFR1 ligand FGF11. This axis is not present in IDH mutant gliomas, associated with hypermethylation and repressed gene expression of the relevant chemokine genes. Our large-scale single-cell analysis elucidated unique MDSC populations that may facilitate GBM progression and mediate tumor immunosuppression. Overall design: Patients were prospectively enrolled into this study at Johns Hopkins Hospital. Written informed consent was provided by all participants according to approved Institutional Review Board Protocol. Fresh tumor tissue and blood were collected at the time of surgery following confirmation of primary glial neoplasm on frozen section. None of the patients was treated with chemotherapy or radiation prior to tumor resection. Tumor samples span all glioma stages (Grade II, Grade III, and Grade IV). Patients undergoing anterior temporal lobectomy for seizure control were consented and non-neoplastic tissue from anterior temporal lobectomy resection was collected as control. Two patients were analyzed using spatial transcriptomics.