Sex and anti-glioma immunity

Abstract Glioblastomas (GBMs) are aggressive, inevitably lethal brain tumors that are massively infiltrated by myeloid cells supporting tumor growth. The main myeloid cell populations encompass brain-resident microglia, bone marrow (BM)-derived monocytes/macrophages and dendritic cells. Interestingly, patients with glioblastoma show sex-dependent differences in the incidence rate (male-to-female ratio of 1.6:1 in GBMs and 2:1 in most malignant mesenchymal GBMs), transcriptomic profiles and patient responses to a standard therapy. Sex-related differences such as higher expression of pro-inflammatory genes in female microglia and stronger upregulation of MHCII coding genes in microglia from male GL261-bearing mice were detected (Ochocka et al. 2021). We employed Cellular Indexing of Transcriptomes and Epitopes by sequencing (CITE-seq) to reliably dissect myeloid cell identities, states and evaluate dynamics of myeloid infiltration during progression of murine GL261 gliomas. We demonstrate the diversity of myeloid cells within the glioma microenvironment: glioma-activated microglia are the major source of cytokines attracting other immune cells, whereas BM-derived cells show the monocyte-to-macrophage transition and immunosuppressive phenotypes. This transition is coupled with a phenotypic switch from the IFN-related to antigen-presentation and tumor-supportive signatures. Moreover, we found striking sex-dependent differences in transcriptional programs and composition of myeloid cells in gliomas. Higher abundance of protumor macrophages in males correlated with greater tumor size. Re-analysis of single-cell omics data from human GBMs revealed the predominance of inflammatory monocytes in female GBMs and abundance of protumor macrophages in male GBMs. Our findings expand understanding of the complexity of anti-tumor immune responses in gliomas and may guide future therapies in consideration of patient sex. Studies supported by National Science Centre Poland research grants PRELUDIUM16 2018/31/N/NZ3/01696, OPUS 14 2017/27/B/NZ3/01605 and 2020/39/B/NZ4/02683.