Hijacking Sexual Immuno-Privilege in GBM—An Immuno-Evasion Strategy

Sharpe, Martyn A.; Baskin, David S.; Jenson, Amanda V.; Baskin, Alexandra M.

doi:10.3390/ijms222010983

Cited by 9 publications

(21 citation statements)

References 168 publications

(237 reference statements)

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“…This abolishes the gender effect on the action of this receptor. The synthesis of androgens by GBM cells itself may be associated with the migration of RORC-Treg cells (regulatory T cells with the related orphan receptor C) into the tumor niche and the formation of an immunosuppressive microenvironment, further facilitating tumor growth [ 36 ]. The hypoxia present in the GBM tumor further enhances the transformation of T Th17 into RORC-Treg [ 37 ].…”

Section: Discussionmentioning

confidence: 99%

Androgen Receptor Expression in the Various Regions of Resected Glioblastoma Multiforme Tumors and in an In Vitro Model

Simińska

Korbecki

Kojder

et al. 2022

IJMS

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Glioblastoma multiforme (GBM) is a malignant glioma, difficult to detect and with the lowest survival rates among gliomas. Its greater incidence among men and its higher survival rate among premenopausal women suggest that it may be associated with the levels of androgens. As androgens stimulate the androgen receptor (AR), which acts as a transcription factor, the aim of this study was the investigate the role of AR in the progression of GBM. The study was conducted on tissues collected from three regions of GBM tumors (tumor core, enhancing tumor region, and peritumoral area). In addition, an in vitro experiment was conducted on U-87 cells under various culture conditions (necrotic, hypoxic, and nutrient-deficient), mimicking the conditions in a tumor. In both of the models, androgen receptor expression was determined at the gene and protein levels, and the results were confirmed by confocal microscopy and immunohistochemistry. AR mRNA expression was higher under nutrient-deficient conditions and lower under hypoxic conditions in vitro. However, there were no differences in AR protein expression. No differences in AR mRNA expression were observed between the tested tumor structures taken from patients. No differences in AR mRNA expression were observed between the men and women. However, AR protein expression in tumors resected from patients was higher in the enhancing tumor region and in the peritumoral area than in the tumor core. In women, higher AR expression was observed in the peritumoral area than in the tumor core. AR expression in GBM tumors did not differ significantly between men and women, which suggests that the higher incidence of GBM in men is not associated with AR expression. In the group consisting of men and women, AR expression varied between the regions of the tumor: AR expression was higher in the enhancing tumor region and in the peritumoral area than in the tumor core, showing a dependence on tumor conditions (hypoxia and insufficient nutrient supply).

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Section: Discussionmentioning

confidence: 99%

Androgen Receptor Expression in the Various Regions of Resected Glioblastoma Multiforme Tumors and in an In Vitro Model

Simińska

Korbecki

Kojder

et al. 2022

IJMS

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“…The supportive influence of microglial cells on glioma growth is now established beyond doubt and can even be reproduced in a xenograft model [ 52 ]. Interestingly, microglia seem to exert a sex-specific influence in the TME [ 53 ] which may help to explain why GBM is more common and aggressive in male patients. In fact, the hijacking of sexual immune privilege by GBM has been identified as an immune evasion strategy of the glioma [ 53 , 54 , 55 ].…”

Section: Heterogeneity Of Cells In Tmementioning

confidence: 99%

“…Interestingly, microglia seem to exert a sex-specific influence in the TME [ 53 ] which may help to explain why GBM is more common and aggressive in male patients. In fact, the hijacking of sexual immune privilege by GBM has been identified as an immune evasion strategy of the glioma [ 53 , 54 , 55 ].…”

Section: Heterogeneity Of Cells In Tmementioning

confidence: 99%

Microglia and Brain Macrophages as Drivers of Glioma Progression

Zheng

Graeber

2022

IJMS

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Evidence is accumulating that the tumour microenvironment (TME) has a key role in the progression of gliomas. Non-neoplastic cells in addition to the tumour cells are therefore finding increasing attention. Microglia and other glioma-associated macrophages are at the centre of this interest especially in the context of therapeutic considerations. New ideas have emerged regarding the role of microglia and, more recently, blood-derived brain macrophages in glioblastoma (GBM) progression. We are now beginning to understand the mechanisms that allow malignant glioma cells to weaken microglia and brain macrophage defence mechanisms. Surface molecules and cytokines have a prominent role in microglia/macrophage-glioma cell interactions, and we discuss them in detail. The involvement of exosomes and microRNAs forms another focus of this review. In addition, certain microglia and glioma cell pathways deserve special attention. These “synergistic” (we suggest calling them “Janus”) pathways are active in both glioma cells and microglia/macrophages where they act in concert supporting malignant glioma progression. Examples include CCN4 (WISP1)/Integrin α6β1/Akt and CHI3L1/PI3K/Akt/mTOR. They represent attractive therapeutic targets.

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“…Our prior analysis of glioblastoma (GBM) transcriptomes highlighted the expression of genes involved in the syntheses of estrogens and androgens. These steroids create immunosuppressive niches and allow GBMs to express reproduction-related proteins that evoke immune privilege [ 1 ].…”

Section: Introductionmentioning

confidence: 99%

“…Control of PGD 2 /PGF 2 ratios: Since hypoxia/hypoxia-inducible factor (HIF) signaling downregulates AKR1C3 expression, PGD 2 /F 2 ratios should correlate with hypoxic/normoxic conditions [ 49 , 50 ]. Estrogen/estrogen receptor-β signaling elevates AKR1C3 expression, and it has been previously shown that estrogenic tumors are heavily infiltrated by M2-polarized microglia and macrophages [ 1 , 31 ]. Estrogen is known to elevate CCL18 secretion in M2 macrophages [ 51 ], but it downregulates the expression of complement components, including C3, in normal brain tissue [ 52 ].…”

Section: Introductionmentioning

confidence: 99%

Acquisition of Immune Privilege in GBM Tumors: Role of Prostaglandins and Bile Salts

Sharpe

Baskin

Johnson

et al. 2023

IJMS

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Based on the postulate that glioblastoma (GBM) tumors generate anti-inflammatory prostaglandins and bile salts to gain immune privilege, we analyzed 712 tumors in-silico from three GBM transcriptome databases for prostaglandin and bile synthesis/signaling enzyme-transcript markers. A pan-database correlation analysis was performed to identify cell-specific signal generation and downstream effects. The tumors were stratified by their ability to generate prostaglandins, their competency in bile salt synthesis, and the presence of bile acid receptors nuclear receptor subfamily 1, group H, member 4 (NR1H4) and G protein-coupled bile acid receptor 1 (GPBAR1). The survival analysis indicates that tumors capable of prostaglandin and/or bile salt synthesis are linked to poor outcomes. Tumor prostaglandin D2 and F2 syntheses are derived from infiltrating microglia, whereas prostaglandin E2 synthesis is derived from neutrophils. GBMs drive the microglial synthesis of PGD2/F2 by releasing/activating complement system component C3a. GBM expression of sperm-associated heat-shock proteins appears to stimulate neutrophilic PGE2 synthesis. The tumors that generate bile and express high levels of bile receptor NR1H4 have a fetal liver phenotype and a RORC-Treg infiltration signature. The bile-generating tumors that express high levels of GPBAR1 are infiltrated with immunosuppressive microglia/macrophage/myeloid-derived suppressor cells. These findings provide insight into how GBMs generate immune privilege and may explain the failure of checkpoint inhibitor therapy and provide novel targets for treatment.

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Hijacking Sexual Immuno-Privilege in GBM—An Immuno-Evasion Strategy

Cited by 9 publications

References 168 publications

Androgen Receptor Expression in the Various Regions of Resected Glioblastoma Multiforme Tumors and in an In Vitro Model

Androgen Receptor Expression in the Various Regions of Resected Glioblastoma Multiforme Tumors and in an In Vitro Model

Microglia and Brain Macrophages as Drivers of Glioma Progression

Acquisition of Immune Privilege in GBM Tumors: Role of Prostaglandins and Bile Salts

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