Asthma reduces glioma formation by T cell decorin-mediated inhibition of microglia

AbstractTo elucidate the mechanisms underlying the reduced incidence of brain tumors in children with Neurofibromatosis type 1 (NF1) and asthma, we leverage Nf1 optic pathway glioma (Nf1OPG) mice, human and mouse RNAseq data, and two different experimental asthma models. Following ovalbumin or house dust mite asthma induction at 4–6 weeks of age (WOA), Nf1OPG mouse optic nerve volumes and proliferation are decreased at 12 and 24 WOA, indicating no tumor development. This inhibition is accompanied by reduced expression of the microglia-produced optic glioma mitogen, Ccl5. Human and murine T cell transcriptome analyses reveal that inhibition of microglia Ccl5 production results from increased T cell expression of decorin, which blocks Ccl4-mediated microglia Ccl5 expression through reduced microglia NFκB signaling. Decorin or NFκB inhibitor treatment of Nf1OPG mice at 4–6 WOA inhibits tumor formation at 12 WOA, thus establishing a potential mechanistic etiology for the attenuated glioma incidence observed in children with asthma.

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Single-cell transcriptomes of pancreatic preinvasive lesions and cancer reveal acinar metaplastic cells’ heterogeneity

Nature Communications ◽

10.1038/s41467-020-18207-z ◽

2020 ◽

Vol 11 (1) ◽

Cited By ~ 1

Author(s):

Yehuda Schlesinger ◽

Oshri Yosefov-Levi ◽

Dror Kolodkin-Gal ◽

Roy Zvi Granit ◽

Luriano Peters ◽

...

Keyword(s):

Single Cell ◽

Malignant Lesion ◽

Tumor Development ◽

Initial Step ◽

Cell Types ◽

Tumor Formation ◽

Specific Cell ◽

Preinvasive Lesions ◽

Cell Transcriptome ◽

Single Cell Transcriptome

Abstract Acinar metaplasia is an initial step in a series of events that can lead to pancreatic cancer. Here we perform single-cell RNA-sequencing of mouse pancreas during the progression from preinvasive stages to tumor formation. Using a reporter gene, we identify metaplastic cells that originated from acinar cells and express two transcription factors, Onecut2 and Foxq1. Further analyses of metaplastic acinar cell heterogeneity define six acinar metaplastic cell types and states, including stomach-specific cell types. Localization of metaplastic cell types and mixture of different metaplastic cell types in the same pre-malignant lesion is shown. Finally, single-cell transcriptome analyses of tumor-associated stromal, immune, endothelial and fibroblast cells identify signals that may support tumor development, as well as the recruitment and education of immune cells. Our findings are consistent with the early, premalignant formation of an immunosuppressive environment mediated by interactions between acinar metaplastic cells and other cells in the microenvironment.

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Immune deconvolution and temporal mapping identifies stromal targets and developmental intervals for abrogating murine low-grade optic glioma formation

Neuro-Oncology Advances ◽

10.1093/noajnl/vdab194 ◽

2021 ◽

Author(s):

Amanda de Andrade Costa ◽

Jit Chatterjee ◽

Olivia Cobb ◽

Elizabeth Cordell ◽

Astoria Chao ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Function ◽

Immune Cell ◽

Tumor Formation ◽

Optic Glioma ◽

Low Grade ◽

Dependent Manner ◽

Cancer Predisposition Syndrome

Abstract Background Brain tumor formation and progression are dictated by cooperative interactions between neoplastic and non-neoplastic cells. This stromal dependence is nicely illustrated by tumors arising in the Neurofibromatosis type 1 (NF1) cancer predisposition syndrome, where children develop low-grade optic pathway gliomas (OPGs). Using several authenticated Nf1-OPG murine models, we previously demonstrated that murine Nf1-OPG growth is regulated by T cell function and microglia Ccl5 production, such that their inhibition reduces tumor proliferation in vivo. While these interactions are critical for established Nf1-OPG tumor growth, their importance in tumor formation has not been explored. Methods A combination of bulk and single cell RNA mouse optic nerve sequencing, immunohistochemistry, T cell assays, and pharmacologic and antibody-mediated inhibition methods were used in these experiments. Results We show that T cells and microglia are the main non-neoplastic immune cell populations in both murine and human LGGs. Moreover, we demonstrate that CD8 + T cells, the predominant LGG-infiltrating lymphocyte population, are selectively recruited through increased Ccl2 receptor (Ccr4) expression in CD8 +, but not CD4 +, T cells, in a NF1/RAS-dependent manner. Finally, we identify the times during gliomagenesis when microglia Ccl5 production (3-6 weeks of age) and Ccl2-mediated T cell infiltration (7-10 weeks of age) occur, such that temporally-restricted Ccl2 or Ccl5 inhibition abrogates tumor formation >3.5 months following the cessation of treatment. Conclusions Collectively, these findings provide proof-of-concept demonstrations that targeting stromal support during early gliomagenesis durably blocks murine LGG formation.

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Non-Coding RNA and Tumor Development in Neurofibromatosis Type 1: ANRIL Rs2151280 Is Associated with Optic Glioma Development and a Mild Phenotype in Neurofibromatosis Type 1 Patients

Genes ◽

10.3390/genes10110892 ◽

2019 ◽

Vol 10 (11) ◽

pp. 892 ◽

Cited By ~ 2

Author(s):

Viviana Tritto ◽

Luca Ferrari ◽

Silvia Esposito ◽

Paola Zuccotti ◽

Donatella Bianchessi ◽

...

Keyword(s):

Neurofibromatosis Type 1 ◽

Tumor Development ◽

Neurofibromatosis Type ◽

Regulatory Function ◽

Circular Rnas ◽

Optic Glioma ◽

Mild Phenotype ◽

Peripheral Nerve Sheath Tumors ◽

Associated Tumors

Non-coding RNAs (ncRNAs) are known to regulate gene expression at the transcriptional and post-transcriptional levels, chromatin remodeling, and signal transduction. The identification of different species of ncRNAs, microRNAs (miRNAs), circular RNAs (circRNAs), and long ncRNAs (lncRNAs)—and in some cases, their combined regulatory function on specific target genes—may help to elucidate their role in biological processes. NcRNAs’ deregulation has an impact on the impairment of physiological programs, driving cells in cancer development. We here carried out a review of literature concerning the implication of ncRNAs on tumor development in neurofibromatosis type 1 (NF1), an inherited tumor predisposition syndrome. A number of miRNAs and a lncRNA has been implicated in NF1-associated tumors, such as malignant peripheral nerve sheath tumors (MPNSTs) and astrocytoma, as well as in the pathognomonic neurofibromas. Some authors reported that the lncRNA ANRIL was deregulated in the blood of NF1 patients with plexiform neurofibromas (PNFs), even if its role should be further elucidated. We here provided original data concerning the association of a specific genotype about ANRIL rs2151280 with the presence of optic gliomas and a mild expression of the NF1 phenotype. We also detected the LOH of ANRIL in different tumors from NF1 patients, supporting the involvement of ANRIL in some NF1-associated tumors. Our results suggest that ANRIL rs2151280 may be a potential diagnostic and prognostic marker, addressing early diagnosis of optic glioma and predicting the phenotype severity in NF1 patients.

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Moyamoya phenomenon after radiation for optic glioma

Journal of Neurosurgery ◽

10.3171/jns.1993.79.1.0032 ◽

1993 ◽

Vol 79 (1) ◽

pp. 32-35 ◽

Cited By ~ 93

Author(s):

John R. W. Kestle ◽

Harold J. Hoffman ◽

Antonio R. Mock

Keyword(s):

Moyamoya Disease ◽

Treatment Plan ◽

Neurofibromatosis Type ◽

Optic Pathway Glioma ◽

Optic Glioma ◽

Optic Pathway ◽

Content Type ◽

Sick Children ◽

Moyamoya Phenomenon ◽

Fine Print

✓ The role of radiotherapy in the management of patients with optic pathway glioma is controversial. In a series of patients with optic pathway glioma treated at The Hospital for Sick Children in Toronto, five children were encountered who developed moyamoya phenomenon after radiotherapy. A retrospective review of the medical records was undertaken in order to assess the relationship between optic pathway glioma, neurofibromatosis type 1 (NF1), radiation therapy, and moyamoya disease. Forty-seven patients with optic pathway glioma were operated on at The Hospital for Sick Children between 1971 and 1990. The moyamoya phenomenon did not occur in any of the 19 patients not receiving radiotherapy. Among the 28 patients who received radiotherapy, five developed moyamoya disease (two of 23 without NF1 and three of five with NF1). There was a statistically significant relationship between radiotherapy and moyamoya disease when the analysis was stratified according to the presence of NF1 (Mantel-Haensel chi-squared test 15.23, p < 0.01). The high incidence of moyamoya disease (three of five cases, or 60%) in patients with NF1 who have undergone radiotherapy suggests a synergistic relationship that should be considered when formulating a treatment plan for NF1 patients with optic pathway glioma.

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Transient genomic instability drives tumorigenesis through accelerated clonal evolution

10.1101/2020.11.17.387753 ◽

2020 ◽

Author(s):

Ofer Shoshani ◽

Bjorn Bakker ◽

Yin Wang ◽

Dong Hyun Kim ◽

Marcus Maldonado ◽

...

Keyword(s):

T Cell ◽

Spindle Assembly Checkpoint ◽

Human Cancer ◽

Clonal Evolution ◽

Chromosome Instability ◽

Tumor Development ◽

Cell Receptor ◽

Tumor Formation ◽

T Cell Lymphomas ◽

End Stage

AbstractAbnormal numerical and structural chromosome content is frequently found in human cancer. To test the role of aneuploidy in tumor initiation and progression, we compared tumor development in mice with chronic chromosome instability (CIN) induced by inactivation of the spindle assembly checkpoint (produced by Mad2 deficiency) and mice with transient CIN through transiently increased expression of polo-like kinase 4 (PLK4), a master regulator of centrosome number. Tumors forming under chronic CIN gradually trended toward chromosomal gains producing a specific karyotype profile that could only be partially maintained in end-stage tumors, as determined by single-cell whole genome DNA sequencing. Short term CIN from transient PLK4 induction generated significant centrosome amplification and aneuploidy resulting in formation of aggressive T cell lymphomas in mice with heterozygous inactivation of one p53 allele or accelerated tumor development in the absence of p53. Transient CIN increased the frequency of lymphomainitiating cells (as revealed by T cell receptor sequencing) with a specific karyotype profile containing triploid chromosomes 4, 5, 14, and 15 occurring early in tumorigenesis. Overall, our evidence demonstrates that distinct CIN mechanisms drive cancers presenting specific, complex chromosomal alterations with transient CIN rapidly enhancing tumor formation by accelerating the generation of such events.

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Dural Ectasia of the Optic Nerve: A Rare Presentation in Neurofibromatosis Type I

Journal of Neurosciences in Rural Practice ◽

10.4103/jnrp.jnrp_232_18 ◽

2019 ◽

Vol 10 (02) ◽

pp. 349-351

Author(s):

Minhaj Shaikh ◽

Pushpinder Khera ◽

Taruna Yadav ◽

Pawan Garg

Keyword(s):

Optic Nerve ◽

Neurofibromatosis Type ◽

Optic Chiasm ◽

Optic Pathway Glioma ◽

Optic Glioma ◽

Type I ◽

Optic Pathway ◽

Rare Presentation ◽

Dural Ectasia ◽

Magnetic Resonance Imaging Mri

ABSTRACTNeurofibromatosis Type 1 (NF-1) is a common neurocutaneous syndrome with a characteristic spectrum of pathologies affecting the optic pathway. Optic pathway glioma and optic nerve meningioma are two such common afflictions of the optic nerve in NF-1. Dural ectasia of the optic nerve also known as optic nerve meningocele is a rare manifestation of optic nerve involvement in NF-1. Magnetic resonance imaging (MRI) is an excellent modality to accurately identify, characterize, delineate, and differentiate dural ectasia of the optic nerve from the commoner lesions such as optic glioma and meningioma in NF-1. We describe a case of a young woman with NF and a large recurrent palpebral neurofibroma. MRI evaluation of the orbits revealed extensive ectasia of the dura lining the cerebrospinal fluid sheath around all the segments of the optic nerve and around the optic chiasm.

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Plasma cell expression of CD28 and CD40 correlates with peripheral T-cell defects in multiple myeloma

Immunology Letters ◽

10.1016/s0165-2478(97)88679-8 ◽

1997 ◽

Vol 56 (1-3) ◽

pp. 452

Author(s):

V Redoglia

Keyword(s):

Multiple Myeloma ◽

T Cell ◽

Plasma Cell ◽

Cell Expression

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Combining mTOR Inhibitors and T Cell-Based Immunotherapies in Cancer Treatment

Cancers ◽

10.3390/cancers13061359 ◽

2021 ◽

Vol 13 (6) ◽

pp. 1359

Author(s):

Alexandre el Hage ◽

Olivier Dormond

Keyword(s):

Immune Response ◽

T Cell ◽

Antitumor Immunity ◽

Tumor Development ◽

Mtor Inhibitors ◽

Resistance Mechanisms ◽

Cancer Cell Growth ◽

Anticancer Effects ◽

Therapeutic Opportunity ◽

Control Tumor

mTOR regulates several processes that control tumor development, including cancer cell growth, angiogenesis and the immune response to tumor. Accordingly, mTOR inhibitors have been thoroughly explored in cancer therapy but have failed to provide long-lasting anticancer benefits. Several resistance mechanisms that counteract the antitumor effect of mTOR inhibitors have been identified and have highlighted the need to use mTOR inhibitors in combination therapies. In this context, emerging evidence has demonstrated that mTOR inhibitors, despite their immunosuppressive properties, provide anticancer benefits to immunotherapies. In fact, mTOR inhibitors also display immunostimulatory effects, in particular by promoting memory CD8+ T cell generation. Hence, mTOR inhibitors represent a therapeutic opportunity to promote antitumor CD8 responses and to boost the efficacy of different modalities of cancer immunotherapy. In this context, strategies to reduce the immunosuppressive activity of mTOR inhibitors and therefore to shift the immune response toward antitumor immunity will be useful. In this review, we present the different classes of mTOR inhibitors and discuss their effect on immune cells by focusing mainly on CD8+ T cells. We further provide an overview of the different preclinical studies that investigated the anticancer effects of mTOR inhibitors combined to immunotherapies.

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