Tubedown Expression Correlates with the Differentiation Status and Aggressiveness of Neuroblastic Tumors

AbstractAdult Schwann cells (SCs) possess an inherent plastic potential. This plasticity allows SCs to acquire repair-specific functions essential for peripheral nerve regeneration. Here, we investigate whether stromal SCs in benign-behaving peripheral neuroblastic tumors adopt a similar cellular state. We profile ganglioneuromas and neuroblastomas, rich and poor in SC stroma, respectively, and peripheral nerves after injury, rich in repair SCs. Indeed, stromal SCs in ganglioneuromas and repair SCs share the expression of nerve repair-associated genes. Neuroblastoma cells, derived from aggressive tumors, respond to primary repair-related SCs and their secretome with increased neuronal differentiation and reduced proliferation. Within the pool of secreted stromal and repair SC factors, we identify EGFL8, a matricellular protein with so far undescribed function, to act as neuritogen and to rewire cellular signaling by activating kinases involved in neurogenesis. In summary, we report that human SCs undergo a similar adaptive response in two patho-physiologically distinct situations, peripheral nerve injury and tumor development.

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Generation of High-Yield, Functional Oligodendrocytes from a c-myc Immortalized Neural Cell Line, Endowed with Staminal Properties

International Journal of Molecular Sciences ◽

10.3390/ijms22031124 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1124

Author(s):

Mafalda Giovanna Reccia ◽

Floriana Volpicelli ◽

Eirkiur Benedikz ◽

Åsa Fex Svenningsen ◽

Luca Colucci-D’Amato

Keyword(s):

Cell Line ◽

Low Cost ◽

Neural Cell ◽

New Drugs ◽

High Yield ◽

Time Saving ◽

Interacting Protein ◽

Neuronal Marker ◽

Differentiation Status

Neural stem cells represent a powerful tool to study molecules involved in pathophysiology of Nervous System and to discover new drugs. Although they can be cultured and expanded in vitro as a primary culture, their use is hampered by their heterogeneity and by the cost and time needed for their preparation. Here we report that mes-c-myc A1 cells (A1), a neural cell line, is endowed with staminal properties. Undifferentiated/proliferating and differentiated/non-proliferating A1 cells are able to generate neurospheres (Ns) in which gene expression parallels the original differentiation status. In fact, Ns derived from undifferentiated A1 cells express higher levels of Nestin, Kruppel-like factor 4 (Klf4) and glial fibrillary protein (GFAP), markers of stemness, while those obtained from differentiated A1 cells show higher levels of the neuronal marker beta III tubulin. Interestingly, Ns differentiation, by Epidermal Growth Factors (EGF) and Fibroblast Growth Factor 2 (bFGF) withdrawal, generates oligodendrocytes at high-yield as shown by the expression of markers, Galactosylceramidase (Gal-C) Neuron-Glial antigen 2 (NG2), Receptor-Interacting Protein (RIP) and Myelin Basic Protein (MBP). Finally, upon co-culture, Ns-A1-derived oligodendrocytes cause a redistribution of contactin-associated protein (Caspr/paranodin) protein on neuronal cells, as primary oligodendrocytes cultures, suggesting that they are able to form compact myelin. Thus, Ns-A1-derived oligodendrocytes may represent a time-saving and low-cost tool to study the pathophysiology of oligodendrocytes and to test new drugs.

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546 The differentiation status of systemic PD1+ CD8 T cells is associated with favorable outcome to PD1 blockade therapy in non small cell lung cancer

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0546 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A582-A582

Author(s):

Asma Khanniche ◽

Ying Wang

Keyword(s):

Lung Cancer ◽

T Cells ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Cd8 T Cells ◽

Small Cell ◽

Favorable Outcome ◽

Small Cell Lung ◽

Differentiation Status ◽

Pd1 Blockade

BackgroundNon small cell lung cancer is one of the cancer types where Immune checkpoint blockade has demonstrated unprecedented clinical efficiency. However, only a fraction of patients benefit from such therapy; factors determining this response are yet to be elucidated. Here, we investigated whether the differentiation status of circulating CD8 T cells might be associated with outcome of PD1 blockade therapy in NSCLC.MethodsWe used multi-parameter flow cytometry to study CD8 T cell differentiation states in NSCLC patients at baseline and to examine the effects of blocking the PD1/PDL1 pathway on those cells.ResultsWe found that responders to PD1 blockade therapy has more peripheral PD1+ CD8 T cells with an early-like differentiated status at baseline and that this phenotype is associated with longer survival. Moreover, PD1 blockade induced reinvigoration is mostly observed in cells with this with an early-like differentiated status.ConclusionsAn early like differentiation status of peripheral CD8 T cells is associated with favorable outcome of PD1 blockade immunotherapy

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Diagnostic Immunohistochemistry of Neuroblastic Tumors

The American Journal of Surgical Pathology ◽

10.1097/00000478-199201000-00007 ◽

1992 ◽

Vol 16 (1) ◽

pp. 56-57 ◽

Cited By ~ 44

Author(s):

G. H. Wirnsberger ◽

H. Becker ◽

Karin Ziervogel ◽

H. Hofler

Keyword(s):

Neuroblastic Tumors

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Deep learning system compared with expert endoscopists in predicting early gastric cancer and its invasion depth and differentiation status (with videos)

Gastrointestinal Endoscopy ◽

10.1016/j.gie.2021.06.033 ◽

2021 ◽

Author(s):

Lianlian Wu ◽

Jing Wang ◽

Xinqi He ◽

Yijie Zhu ◽

Xiaoda Jiang ◽

...

Keyword(s):

Gastric Cancer ◽

Deep Learning ◽

Early Gastric Cancer ◽

Learning System ◽

Invasion Depth ◽

Differentiation Status

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Clinical and Pathological Evidence of Anti-GD2 Immunotherapy Induced Differentiation in Relapsed/Refractory High-Risk Neuroblastoma

Cancers ◽

10.3390/cancers13061264 ◽

2021 ◽

Vol 13 (6) ◽

pp. 1264

Author(s):

Jaume Mora ◽

Alicia Castañeda ◽

Maria Cecilia Colombo ◽

Maite Gorostegui ◽

Fernando Gomez ◽

...

Keyword(s):

High Risk ◽

Fdg Pet ◽

Current Therapy ◽

Bone Lesions ◽

Functional Magnetic Resonance ◽

Positron Emission ◽

Apparent Diffusion ◽

Neuroblastic Tumors ◽

Direct Cell ◽

Magnetic Resonance Imaging Mri

Background: Neuroblastic tumors (NBTs) originate from a block in the process of differentiation. Histologically, NBTs are classified in neuroblastoma (NB), ganglioneuroblastoma (GNB), and ganglioneuroma (GN). Current therapy for high-risk (HR) NB includes chemotherapy, surgery, radiotherapy, and anti-GD2 monoclonal antibodies (mAbs). Anti-GD2 mAbs induce immunological cytoxicity but also direct cell death. Methods: We report on patients treated with naxitamab for chemorefractory NB showing lesions with long periods of stable disease. Target lesions with persisting 123I-Metaiodobenzylguanidine (MIBG) uptake after 4 cycles of immunotherapy were further evaluated by functional Magnetic Resonance Imaging (MRI) and/or Fluorodeoxyglucose (FDG)-positron emission tomography (PET). MIBG avid lesions that became non-restrictive on MRI (apparent diffusion coefficient (ADC) > 1) and/or FDG-PET negative (SUV < 2) were biopsied. Results: Twenty-seven relapse/refractory (R/R) HR-NB patients were enrolled on protocol Ymabs 201. Two (7.5%) of the 27 showed persistent bone lesions on MIBG, ADC high, and/or FDG-PET negative. Forty-four R/R HR-NB patients received chemo-immunotherapy. Twelve (27%) of the 44 developed persistent MIBG+ but FDG-PET- and/or high ADC lesions. Twelve (86%) of the 14 cases identified were successfully biopsied producing 16 evaluable samples. Histology showed ganglioneuroma maturing subtype in 6 (37.5%); ganglioneuroma mature subtype with no neuroblastic component in 4 (25%); differentiating NB with no Schwannian stroma in 5 (31%); and undifferentiated NB without Schwannian stroma in one (6%). Overall, 10 (62.5%) of the 16 specimens were histopathologically fully mature NBTs. Conclusions: Our results disclose an undescribed mechanism of action for naxitamab and highlight the limitations of conventional imaging in the evaluation of anti-GD2 immunotherapy clinical efficacy for HR-NB.

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Endogenous antigen presentation impacts on T-box transcription factor expression and functional maturation of CD8+ T cells

Blood ◽

10.1182/blood-2012-03-420182 ◽

2012 ◽

Vol 120 (16) ◽

pp. 3237-3245 ◽

Cited By ~ 19

Author(s):

Corey Smith ◽

Diah Elhassen ◽

Stephanie Gras ◽

Katherine K. Wynn ◽

Vijayendra Dasari ◽

...

Keyword(s):

T Cells ◽

Transcription Factors ◽

Antigen Presentation ◽

Cd8 T Cells ◽

Viral Antigen ◽

Cytotoxic T Lymphocyte ◽

Granzyme B ◽

T Box ◽

Differentiation Status ◽

Human Cmv

Abstract T-box transcription factors T-bet (Tbx21) and Eomesodermin (Eomes) are critical players in CD8+ cytotoxic T lymphocyte effector function and differentiation, but how the expression of these transcription factors is regulated remains poorly defined. Here we show that dominant T cells directed toward human CMV, expressing significantly higher levels of T-bet with graded loss of Eomes expression (T-bethiEomeshi/lo), are more efficient in recognizing endogenously processed peptide-major histocompatibility complexes (pMHC) compared with subdominant virus-specific T cells expressing lower levels of T-bet and high levels of Eomes (T-betintEomeshi). Paradoxically, the T-bethiEomeshi/lo dominant populations that efficiently recognized endogenous antigen demonstrated lower intrinsic avidity for pMHC, whereas T-betintEomeshi subdominant populations were characterized by higher pMHC avidity and less efficient recognition of virus-infected cells. Importantly, differential endogenous viral antigen recognition by CMV-specific CD8+ T cells also correlated with the differentiation status and expression of perforin, granzyme B and K. Furthermore, we demonstrate that the expression of T-bet correlates with clonal expansion, differentiation status, and expression of perforin, granzyme B and K in antigen-specific T cells. These findings illustrate how endogenous viral antigen presentation during persistent viral infection may influence the transcriptional program of virus-specific T cells and their functional profile in the peripheral blood of humans.

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Multiple Immunofluorescence Imaging Analysis Reveals Differential Expression of Disialogangliosides GD3 and GD2 in Neuroblastomas

Pediatric and Developmental Pathology ◽

10.1177/10935266211048733 ◽

2021 ◽

pp. 109352662110487

Author(s):

Haruna Nishimaki ◽

Yoko Nakanishi ◽

Hiroshi Yagasaki ◽

Shinobu Masuda

Keyword(s):

High Risk ◽

Risk Group ◽

Staging System ◽

Low Risk ◽

Overall Survival Rate ◽

Imaging Analysis ◽

Tissue Samples ◽

Risk Patients ◽

Neuroblastic Tumors ◽

Expression Status

Background Peripheral neuroblastic tumors (pNTs) are the most common childhood extracranial solid tumors. There are several therapeutic strategies targeting disialoganglioside GD2. Disialoganglioside GD3 has become a potential target. However, the mechanism by which pNTs express GD3 and GD2 remains unclear. We investigated the combined expression status of GD3 and GD2 in pNTs and delineated their clinicopathological values. Methods GD3 and GD2 expression was examined in pNT tissue samples (n = 35) using immunohistochemistry and multiple immunofluorescence imaging. Results GD3 and GD2 expression was positive in 32/35 and 25/35 samples, respectively. Combinatorial analysis of GD3 and GD2 expression in neuroblastoma showed that both were heterogeneously expressed from cell to cell. There were higher numbers of GD3-positive and GD2-negative cells in the low-risk group than in the intermediate-risk ( P = 0.014) and high-risk ( P = 0.009) groups. Cases with high proportions of GD3-positive and GD2-negative cells were associated with the International Neuroblastoma Staging System stage ( P = 0.004), Children’s Oncology Group risk group ( P = 0.001), and outcome ( P = 0.019) and tended to have a higher overall survival rate. Conclusion We demonstrated that neuroblastomas from low-risk patients included more GD3-positive and GD2-negative cells than those from high-risk patients. Clarifying the heterogeneity of neuroblastoma aids in better understanding the biological characteristics and clinical behavior.

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