Tumor-associated reactive astrocytes aid the evolution of immunosuppressive environment in glioblastoma

Abstract

Reactive astrocytes evolve after brain injury, inflammatory and degenerative diseases, whereby they undergo transcriptomic re-programming. In malignant brain tumors, their function and crosstalk to other components of the environment is poorly understood. Here we report a distinct transcriptional phenotype of reactive astrocytes from glioblastoma linked to JAK/STAT pathway activation. Subsequently, we investigate the origin of astrocytic transformation by a microglia loss-of-function model in a human organotypic slice model with injected tumor cells. RNA-seq based gene expression analysis of astrocytes reveals a distinct astrocytic phenotype caused by the coexistence of microglia and astrocytes in the tumor environment, which leads to a large release of anti-inflammatory cytokines such as TGFβ, IL10 and G-CSF. Inhibition of the JAK/STAT pathway shifts the balance of pro- and anti-inflammatory cytokines towards a pro-inflammatory environment. The complex interaction of astrocytes and microglia cells promotes an immunosuppressive environment, suggesting that tumor-associated astrocytes contribute to anti-inflammatory responses.

Pathogenesis of peritumoral hyperexcitability in an immunocompetent CRISPR-based glioblastoma model

“…These results raise the possibility that although MMP secretion by tumor cells is one candidate mechanism for PNN degradation in regions within the tumor, microglial infiltration near and far away from the tumor (contralateral cortex) could also contribute to PNN degradation and facilitate the transition from peritumoral hyperexcitability to generalized seizure activity. Other specific mechanistic relationships remain to be evaluated; for example, we also found evidence of moderate reactive astrocytosis at onset and late disease stages (Supplemental Figure 4), which has been linked to epileptogenesis (43), yet conversely, has been proposed to exert an antiinflammatory influence in the tumoral milieu (44).…”

Autophagy in the Immunosuppressive Perivascular Microenvironment of Glioblastoma

“…Specifically, it is well known that the brain tumor microenvironment is characterized by secretion of a variety of anti-inflammatory molecules, not only by tumor cells themselves, but also by other surrounding peritumoral cells previously conditioned by the tumor. These peritumoral cells are peripheral immune cells (i.e., tumor-associated macrophages (TAMs), T cells, myeloid-derived suppressor cells (MDSC) and T regulatory cells (Tregs)), and various specialized organ-resident cells including microglial cells, astrocytes and perivascular pericytes (PC) [8,10,13]. Collectively, anti-tumor innate and adaptive immune responses in the tumor microenvironment are altered, and several mechanisms including decreased T cell activation and proliferation, induction of anergic T cells, differentiation of Tregs, down-regulation of major histocompatibility complex (MHC) expression and polarization of macrophages to an immunosuppressive M2 phenotype, are prompted by tumor cells [22,26].…”

“…Reactive astrocytes establish direct cell interactions by gap junctions with tumor cells and microglial cells at the peritumoral glial scar favoring tumor progression and chemoresistance. Astrocytes contacting tumor cells secrete cytokines that support tumor metastasis in the brain and contribute to an immunosuppressive microenvironment with high levels of anti-inflammatory cytokines such as IL-10, TGFβ and CSF [10]. Autophagy/lysosomal dysfunction in astrocytes participates in neurodegeneration as observed in lysosomal storage disorders [127].…”

“…Glioblastoma (GB), the most aggressive brain cancer, evades the immune system [8][9][10][11]. GB cells interact with cells from perivascular areas and invade the brain parenchyma forming a functional network of microtubes [12][13][14][15].…”

Targeting iNOS As a Valuable Strategy for the Therapy of Glioma

“…Interestingly, it did not impair astrocytes viability at the same concentration range, suggesting an important cell selectivity. This molecule has been further investigated, showing that it compromises the adaptive responses in glioma cells involved in chemoresistance, by stimulating PARP‐1 cleavage, and enhancing the effects of TMZ …”