Pediatric Primitive Neuroectodermal Tumors of the Central Nervous System Differentially Express Granzyme Inhibitors

Vermeulen, Jeroen F.; Hecke, Wim Van; Spliet, Wim G.M.; Hidalgo, José Villacorta; Fisch, Paul; Broekhuizen, Roel; Bovenschen, Niels

doi:10.1371/journal.pone.0151465

Cited by 10 publications

(13 citation statements)

References 30 publications

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“…We found that six out of 26 tumors acquired expression of SerpinB1 (23%) and 13 out of 26 tumors SerpinB4 (50%). In contrast to CNS-PNETs, 17 we did not find expression of SerpinB9 in pediatric medulloblastoma ( Fig. 2B ).…”

Section: Resultscontrasting

confidence: 64%

“…Immunohistochemistry was carried out on 4 μm thick formalin fixed paraffin embedded consecutive sections as described before by Vermeulen et al. 17 Immunohistochemistry for PD-1 (Abcam clone NAT105, ab52587) 1:50 and PD-L1 (Abcam clone 28-8, ab205921) 1:50 was performed using an automated immunostainer (Benchmark Ultra, Ventana, Roche). Immunohistochemistry for myeloperoxidase (MPO) (Leica Biosystems Novocastra clone 59A5) was performed manually.…”

Section: Methodsmentioning

confidence: 99%

“… 19–21 Recently, we have demonstrated that CNS-PNETs can induce expression of SERPINB1 (GrH inhibitor), SERPINB4 (GrM inhibitor), and SERPINB9 (GrB inhibitor). 17 …”

Section: Introductionmentioning

confidence: 99%

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Prognostic relevance of tumor-infiltrating lymphocytes and immune checkpoints in pediatric medulloblastoma

et al. 2017

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Pediatric medulloblastomas are the most frequently diagnosed embryonal tumors of the central nervous system. Current therapies cause severe neurological and cognitive side effects including secondary malignancies. Cellular immunotherapy might be key to improve survival and to avoid morbidity. Efficient killing of tumor cells using immunotherapy requires to overcome cancer-associated strategies to evade cytotoxic immune responses. Here, we examined the immune response and immune evasion strategies in pediatric medulloblastomas. Cytotoxic T-cells, infiltrating medulloblastomas with variable activation status, showed no correlation with overall survival of the patients. We found limited numbers of PD1+ T-cells and complete absence of PD-L1 on medulloblastomas. Medulloblastomas downregulated immune recognition molecules MHC-I and CD1 d. Intriguingly, expression of granzyme inhibitors SERPINB1 and SERPINB4 was acquired in 23% and 50% of the tumors, respectively. Concluding, pediatric medulloblastomas exploit multiple immune evasion strategies to overcome immune surveillance. Absence of PD-L1 expression in medulloblastoma suggest limited or no added value for immunotherapy with PD1/PD-L1 blockers.

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Section: Resultscontrasting

confidence: 64%

Section: Methodsmentioning

confidence: 99%

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Prognostic relevance of tumor-infiltrating lymphocytes and immune checkpoints in pediatric medulloblastoma

et al. 2017

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“…It is also expressed in accessory immune cells, such as dendritic cells, where it plays a role in presenting antigens 67 . SERPINB9 could contribute to immune evasion in leukemia cells 68 and to overcoming intracellular cytotoxicity in neuroectodermal tumors 69 . It has also been involved in autoimmune diseases 70 , such as celiac disease 71 .…”

Section: Discussionmentioning

confidence: 99%

Telomere length correlates with subtelomeric DNA methylation in long-term mindfulness practitioners

Mendioroz

Puebla‐Guedea

Montero-Marín

et al. 2020

Sci Rep

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Mindfulness and meditation techniques have proven successful for the reduction of stress and improvement in general health. In addition, meditation is linked to longevity and longer telomere length, a proposed biomarker of human aging. Interestingly, DNA methylation changes have been described at specific subtelomeric regions in long-term meditators compared to controls. However, the molecular basis underlying these beneficial effects of meditation on human health still remains unclear. Here we show that DNA methylation levels, measured by the Infinium HumanMethylation450 BeadChip (Illumina) array, at specific subtelomeric regions containing GPR31 and SERPINB9 genes were associated with telomere length in long-term meditators with a strong statistical trend when correcting for multiple testing. Notably, age showed no association with telomere length in the group of long-term meditators. These results may suggest that long-term meditation could be related to epigenetic mechanisms, in particular gene-specific DNA methylation changes at distinct subtelomeric regions.

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“…Inhibition of mTOR potently induced IDO1 expression and activity, corroborating its ability to recruit Treg cells in the tumor microenvironment, which is the mechanism by which mTOR-targeted therapy fails. More recently, one report showed that central nervous system primitive neuroectodermal tumors are capable of evading immune recognition by downregulating the expression of their cell surface MHC-I and CD1d, and by overexpressing granzyme inhibitors SERPINB9, SERPINB1, and SERPINB4 [85]. Another study found that genetically downregulating Treg TGF-β signaling nearly abolished Treg cells and inhibited medulloblastoma progression via CD8 + cytotoxic T-lymphocyte attack [86].…”

Section: Immune Evasionmentioning

confidence: 99%

Brain Cancer Stem Cells in Adults and Children: Cell Biology and Therapeutic Implications

et al. 2017

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Brain tumors represent some of the most malignant cancers in both children and adults. Current treatment options target the majority of tumor cells but do not adequately target self-renewing cancer stem cells (CSCs). CSCs have been reported to resist the most aggressive radiation and chemotherapies, and give rise to recurrent, treatment-resistant secondary malignancies. With advancing technologies, we now have a better understanding of the genetic, epigenetic and molecular signatures and microenvironmental influences which are useful in distinguishing between distinctly different tumor subtypes. As a result, efforts are now underway to identify and target CSCs within various tumor subtypes based on this foundation. This review discusses progress in CSC biology as it relates to targeted therapies which may be uniquely different between pediatric and adult brain tumors. Studies to date suggest that pediatric brain tumors may benefit more from genetic and epigenetic targeted therapies, while combination treatments aimed specifically at multiple molecular pathways may be more effective in treating adult brain tumors which seem to have a greater propensity towards microenvironmental interactions. Ultimately, CSC targeting approaches in combination with current clinical therapies have the potential to be more effective owing to their ability to compromise CSCs maintenance and the mechanisms which underlie their highly aggressive and deadly nature.

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Pediatric Primitive Neuroectodermal Tumors of the Central Nervous System Differentially Express Granzyme Inhibitors

Cited by 10 publications

References 30 publications

Prognostic relevance of tumor-infiltrating lymphocytes and immune checkpoints in pediatric medulloblastoma

Prognostic relevance of tumor-infiltrating lymphocytes and immune checkpoints in pediatric medulloblastoma

Telomere length correlates with subtelomeric DNA methylation in long-term mindfulness practitioners

Brain Cancer Stem Cells in Adults and Children: Cell Biology and Therapeutic Implications

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