Biology subjects

Cyranowski, S.

Publications and source records attributed to Cyranowski, S..

3 recordsLinked to original sources

bioRxiv2024

Hypoxic stress dysregulates functions of glioma-associated myeloid cells through epigenomic and transcriptional programs

Hypoxia rapidly alters gene expression to allow cellular adaptation to challenging conditions and support tumour growth. Hypoxia also affects the chromatin structure by modifications of histones and DNA methylation. Glioblastoma (GBM) is an aggressive, deadly primary brain tumour for which there is no effective treatment. The tumour microenvironment of GBM is highly heterogeneous, with infiltration of glioma-associated microglia and macrophages (GAMs) and the presence of necrotic, hypoxic regions which significantly impair effectiveness of therapies. The mechanisms through which hypoxia alters the tumour microenvironment and regulates functions of infiltrating immune cells remain poorly understood. Here, we show that hypoxia modulates the expression of myeloid markers in distinct ways: upregulates the expression of monocytic marker Lgals3 and downregulates the microglial markers P2ry12 and Tmem119 in microglial and monocytic GAMs in vitro and in vivo. Underlying genome-wide hypoxia-dependent transcriptomic changes in microglial cells were identified using microglia-glioma co-cultures and validated in human and mouse GBM single- cell transcriptomics datasets. Numerous GAM subtype markers are dysregulated in response to hypoxic stress due to associated changes in chromatin accessibility, as determined using ATACseq. While hypoxia alone drives a decrease of the overall chromatin accessibility at gene promoters, the exposure to glioma cells under hypoxic conditions leads to both increases and decreases of chromatin accessibility at promoter regions in microglial cells. Hypoxia downregulates the chromatin accessibility at the regions enriched in motifs for transcription factors known as master regulators of microglial cell identity and function, including SPI1 or IRF8. Overall, our results highlight the importance of hypoxic stress as a strong intratumoral regulator of myeloid cell functions, which adds a new dimension to the characterisation of particular GAM subpopulations.

cancer biology↗

bioRxiv2024

Integrin blocking peptide reverses immunosuppression in experimental gliomas and improves anti-PD-1 therapy outcome

Immune checkpoint inhibitors (ICI) presented clinical benefits in many cancer patients but invariably fail in glioblastoma (GBM), the most common and deadly primary brain tumor. Lack of ICI efficacy in GBM is attributed to the accumulation of immunosuppressive myeloid cells that create the "cold" tumor microenvironment (TME) impeding infiltration and activation of effector T cells. We developed a designer RGD peptide that hindered glioma-instigated, integrin-mediated pro-tumoral reprogramming of myeloid cells and blocked microglia-dependent invasion of human and mouse glioma cells in co-cultures in vitro. Intratumorally-delivered RGD alone did not reduce glioma growth in syngeneic mice but prevented the emergence of immunosuppressive myeloid cells and led to peritumoral blood vessels normalization. Furthermore, combining RGD with immunotherapy using PD-1 blockade reduced tumor growth, led to upsurge of proliferating, interferon-{gamma} producing CD8+T cells and depleted regulatory T cells. Transcriptomic profiles of myeloid cells were altered by the combined treatment, consistently with the restored "hot" inflammatory TME and boosted immunotherapy responses. RGD modified the phenotypes of myeloid cells in human gliomas in nude mice. Thus, combining the integrin blockade with ICI reinvigorates antitumor immunity and paves the way to improve immunotherapy outcomes in GBM.

cancer biology↗

bioRxiv2019

Single-cell RNA sequencing reveals functional heterogeneity and sex differences of glioma-associated brain macrophages

Microglia are resident myeloid cells in the central nervous system (CNS) that control homeostasis and protect CNS from damage and infections. Microglia and peripheral myeloid cells accumulate and adapt tumor supporting roles in human glioblastomas that show prevalence in men. Cell heterogeneity and functional phenotypes of myeloid subpopulations in gliomas remain elusive. Single-cell RNA sequencing (scRNA-seq) of CD11b+ myeloid cells in naive and GL261 glioma-bearing mice revealed distinct profiles of microglia, infiltrating monocytes/macrophages and CNS border-associated macrophages. We demonstrated an unforeseen molecular heterogeneity among myeloid cells in naive and glioma-bearing brains, validated selected marker proteins and showed distinct spatial distribution of identified subsets in experimental gliomas. We found higher expression of MHCII encoding genes in glioma-activated male microglia, which was corroborated in bulk and scRNA-seq data from human diffuse gliomas. Sex-specific gene expression in glioma-activated microglia may be relevant to sex differences in incidence and outcomes of glioma patients.

cancer biology↗