scholarly journals Microporous scaffolds loaded with immunomodulatory lentivirus to study the contribution of immune cell populations to tumor cell recruitment in vivo

2019 ◽  
Vol 117 (1) ◽  
pp. 210-222 ◽  
Author(s):  
Grace G. Bushnell ◽  
Shreyas S. Rao ◽  
Rachel M. Hartfield ◽  
Yining Zhang ◽  
Robert S. Oakes ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Immune Cell ◽  
Cell Populations ◽  
Cell Recruitment ◽  
Microporous Scaffolds

scholarly journals In Vivo Effects of Nonoxynol-9 on Endometrial Immune Cell Populations

2009 ◽  
Vol 52 (1) ◽  
pp. 137-139 ◽  
Author(s):  
Lisa Rahangdale ◽  
Ruth M Greenblatt ◽  
Jean Perry ◽  
Teresa M Darragh ◽  
Akiko Kobayashi ◽  
...  
Keyword(s):  
Immune Cell ◽  
Cell Populations ◽  
In Vivo Effects

scholarly journals Small-molecule inhibitor of OGG1 suppresses proinflammatory gene expression and inflammation

Science ◽  
2018 ◽  
Vol 362 (6416) ◽  
pp. 834-839 ◽  
Author(s):  
Torkild Visnes ◽  
Armando Cázares-Körner ◽  
Wenjing Hao ◽  
Olov Wallner ◽  
Geoffrey Masuyer ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Cell ◽  
Nuclear Factor Κb ◽  
Cell Recruitment ◽  
Inflammatory Conditions ◽  
Molecule Inhibitor ◽  
Proinflammatory Gene ◽  
Factor Α ◽  
Proinflammatory Gene Expression

The onset of inflammation is associated with reactive oxygen species and oxidative damage to macromolecules like 7,8-dihydro-8-oxoguanine (8-oxoG) in DNA. Because 8-oxoguanine DNA glycosylase 1 (OGG1) binds 8-oxoG and because Ogg1-deficient mice are resistant to acute and systemic inflammation, we hypothesized that OGG1 inhibition may represent a strategy for the prevention and treatment of inflammation. We developed TH5487, a selective active-site inhibitor of OGG1, which hampers OGG1 binding to and repair of 8-oxoG and which is well tolerated by mice. TH5487 prevents tumor necrosis factor–α–induced OGG1-DNA interactions at guanine-rich promoters of proinflammatory genes. This, in turn, decreases DNA occupancy of nuclear factor κB and proinflammatory gene expression, resulting in decreased immune cell recruitment to mouse lungs. Thus, we present a proof of concept that targeting oxidative DNA repair can alleviate inflammatory conditions in vivo.

scholarly journals Ionizing radiation improves RIG-I mediated immunotherapy through enhanced p53 activation in malignant melanoma

2021 ◽  
Author(s):  
Silke Lambing ◽  
Stefan Holdenrieder ◽  
Patrick Müller ◽  
Christian Hagen ◽  
Stephan Garbe ◽  
...  
Keyword(s):  
Cell Death ◽  
Malignant Melanoma ◽  
Tumor Cell ◽  
Low Dose ◽  
Immune Cell ◽  
Cytotoxic T Cell ◽  
Great Promise ◽  
Type I ◽  
Tumor Cell Death

The activation of the innate immune receptor RIG-I is a promising approach in immunooncology and currently under investigation in clinical trials. RIG-I agonists elicit a strong immune activation in both tumor and immune cells and induce both direct and indirect immune cell-mediated tumor cell death which involves tumor-specific cytotoxic T-cell response and type I interferon-driven innate cytotoxic immunity. Besides RIG-I, irradiation is known to induce cytotoxic DNA damage resulting in tumor debulking followed by the induction of tumor-specific immunity. To date, it is unclear whether the molecular antitumor effects of RIG-I and irradiation are additive or even synergize. Here, we investigated the combination of RIG-I activation with radiotherapy in melanoma. We found that low dose x-ray irradiation enhanced the extent and immunogenicity of RIG-I mediated tumor cell death in human and murine melanoma cell lines and in the murine B16 melanoma model in vivo. Pathway analysis of transcriptomic data revealed a central role for p53 downstream of the combined treatment, which was corroborated using p53-/- B16 cells. In vivo, the additional effect of irradiation on immune cell activation and inhibition of tumor growth was lost in mice carrying p53-knockout B16 tumors, while the response to RIG-I stimulation in those mice was maintained. Thus, our results identify p53 as pivotal for the synergy of RIG-I with irradiation, resulting in potent induction of immunogenic tumor cell death. Consequently, low dose radiotherapy holds great promise to further improve the efficacy or RIG-I ligands especially in patients with malignant melanoma or other tumors exhibiting a functional p53 pathway.

scholarly journals Cannabinoid type 2 receptor (CB2R) distribution in dermatomyositis skin and peripheral blood mononuclear cells (PBMCs) and in vivo effects of LenabasumTM

2022 ◽  
Vol 24 (1) ◽  
Author(s):  
Spandana Maddukuri ◽  
Jay Patel ◽  
De Anna Diaz ◽  
Kristen L. Chen ◽  
Maria Wysocka ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Mononuclear Cells ◽  
Cytokine Production ◽  
Immune Cell ◽  
Cell Populations ◽  
Peripheral Blood Mononuclear ◽  
Blood Mononuclear Cells ◽  
Ifn Γ

Abstract Background Lenabasum is a cannabinoid type 2 receptor (CB2R) reverse agonist that demonstrates anti-inflammatory effects in vivo and in vitro in dermatomyositis (DM) and is currently being investigated for therapeutic potential. The purpose of our study is to investigate CB2R distribution as well as the effects of lenabasum in DM. Methods Immunohistochemistry staining (IHC) was utilized to examine immune cell and cytokine production changes in lesional DM skin biopsies from lenabasum and placebo-treated patients. CB2R expression in various immune cell populations within DM skin was investigated with image mass cytometry (IMC), whereas flow cytometry elucidated CB2R expression in DM peripheral blood mononuclear cells (PBMCs) as well as cytokine production by CB2R-expressing cell populations. Results After 12 weeks of lenabasum treatment, IHC staining showed that CD4+ T cells, CB2R, IL-31, IFN-γ, and IFN-β cytokines were downregulated. IFN-γ and IFN-β mRNA decreased in lesional DM skin but not in PBMCs. IMC findings revealed that CB2R was upregulated in DM lesional skin compared to HC skin and DM PBMCs (p<0.05). In DM skin, CB2R was upregulated on dendritic cells, B cells, T cells, and macrophages while dendritic cells had the greatest expression in both DM skin and PBMCs (p<0.05). These CB2R+ cells in the skin produce IL-31, IL-4, IFN-γ, and IFN-β. Conclusion Our findings of differential CB2R expression based on location and cell type suggest modes by which lenabasum may exert anti-inflammatory effects in DM and highlights dendritic cells as potential therapeutic targets.

Response to primary chemotherapy (CHT) in advanced epithelial ovarian cancer (EOC) patients (pts) and molecular characterization of CHT-resistant tumor cell populations: Findings from the Arianna 02 Project

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 16059-16059
Author(s):  
C. Zamagni ◽  
R. M. Wirtz ◽  
P. De Iaco ◽  
A. Altimari ◽  
K. Roth ◽  
...  
Keyword(s):  
Growth Factor ◽  
Tumor Cell ◽  
Hormone Receptors ◽  
Expression Profiles ◽  
High Response Rate ◽  
Biological Data ◽  
Receptor Expression ◽  
Cell Populations ◽  
Initial Development

16059 Background: Despite a high response rate to CHT the prognosis of pts with advanced EOC remains poor. The molecular analysis of pre- and post-CHT tumor specimen may enable the identification of CHT resistant tumor cell populations and thereby lead to adapted treatment options. Methods: Stage III-IV EOC pts diagnosed by laparoscopy and biopsy and not suitable for optimal debulking surgery were eligible. Gene-expression profiles generated from total RNA using the Affymetrix U133A oligonucleotide microarray containing over 22,000 probe sets were obtained at diagnosis and on surgical specimens after 6 courses of primary carboplatin/paclitaxel CHT. Initial comparative analysis focused on proliferative and invasive tumor activity, and on growth factor- and hormone receptors expression. Results: 30 pts were enrolled and data were analyzed according to response to CHT and to time to relapse after surgery. Initial expression analysis results reveal that the quantitative determination of growth factor- and hormone receptors in pre- and post-treatment samples can be used to discriminate responders from non-responders and relates to clinical outcome. Moreover, multiple CHT-resistant tumor cell populations displayed pronounced estrogen receptor expression suggesting a role of hormone receptors in the development of CHT resistance. Conclusions: While hormonal therapies are used in the treatment of other endocrine related tumors, they are not approved for the treatment of EOC. Treatment of EOC cell lines with estrogens down-regulates GnRH activity and promotes cell growth, while tamoxifen has an opposite effect. However, further biological data are lacking in this setting and only few clinical trials have addressed this possibility so far. We have found that the expression of hormone receptors in vivo persists in CHT-resistant tumor cell populations after CHT for EOC. We suggest that hormone receptor activity contributes to the initial development of CHT resistance; hence endocrine therapies particularly in an early setting may be advantageous to a subset of pts and are worth studying. No significant financial relationships to disclose.

scholarly journals Splice Factor Polypyrimidine tract-binding protein 1 (Ptbp1) is Required for Immune Priming of the Endothelium in Atherogenic Disturbed Flow Conditions

2021 ◽  
Author(s):  
Jessica A Hensel ◽  
Sarah-Anne E Nicholas ◽  
Evan R Jellison ◽  
Amy L Kimble ◽  
Antoine Menoret ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Immune Cell ◽  
Myeloid Cell ◽  
Innate Immune ◽  
Polypyrimidine Tract ◽  
Cell Recruitment ◽  
Polypyrimidine Tract Binding ◽  
Polypyrimidine Tract Binding Protein ◽  
Immune Cell Recruitment

NFkB mediated endothelial activation drives leukocyte recruitment and atherosclerosis, in part through upregulation of adhesion molecules Icam1 and Vcam. The endothelium is primed for cytokine activation of NFkB by exposure to low and disturbed blood flow (LDF) in vivo and by LDF or static conditions in cultured cells. While priming leads to an exaggerated expression of Icam1 and Vcam following cytokine stimulation, the molecular underpinnings are not fully understood. We showed that alternative splicing of genes regulating NFkB signaling occurs during priming, but the functional implications of this are not known. We hypothesize that the regulation of splicing by RNA-binding splice factors is critical for priming. Here, we perform a CRISPR screen in cultured aortic endothelial cells to determine whether splice factors active in the response to LDF participate in endothelial cell priming. Using Icam1 and Vcam induction by TNFalpha stimulation as a marker of priming, we identify polypyrimidine tract binding protein (Ptbp1) as a required splice factor. Ptbp1 expression is increased and its motifs are enriched nearby alternatively spliced exons in endothelial cells exposed to LDF in vivo in a platelet dependent manner, indicating its induction by early innate immune cell recruitment. At a mechanistic level, deletion of Ptbp1 inhibited NFkB nuclear translocation and transcriptional activation. These changes coincided with altered splicing of key components of the NFkB signaling pathway that were similarly altered in the LDF response. However, these splicing and transcriptional changes could be restored by expression of human PTBP1 cDNA in Ptbp1 deleted cells. In vivo, endothelial specific deletion of Ptbp1 reduced myeloid cell infiltration at regions of LDF in atherosclerotic mice. In human coronary arteries, PTBP1 expression correlates with expression of TNF pathway genes and amount of plaque. Together, our data suggest that Ptbp1, which is activated in the endothelium by innate immune cell recruitment in regions of LDF, is required for priming of the endothelium for subsequent NFkB activation and myeloid cell recruitment in vascular inflammation.

scholarly journals Diflunisal targets the HMGB1/CXCL12 heterocomplex and blocks immune cell recruitment

2019 ◽  
Author(s):  
Federica De Leo ◽  
Giacomo Quilici ◽  
Mario Tirone ◽  
Valeria Mannella ◽  
Francesco De Marchis ◽  
...  
Keyword(s):  
Rational Design ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Inflammatory Cells ◽  
Cell Recruitment ◽  
Redox States ◽  
Inflammatory Drugs ◽  
Anti Inflammatory

AbstractExtracellular HMGB1 triggers inflammation following infection or injury, and supports tumorigenesis in inflammation-related malignancies. HMGB1 has several redox states: reduced HMGB1 recruits inflammatory cells to injured tissues forming a heterocomplex with CXCL12 and signaling via its receptor CXCR4; disulfide-containing HMGB1 binds to TLR4 and promotes inflammatory responses. Here we show that Diflunisal, an aspirin-like nonsteroidal anti-inflammatory drug (NSAID) that has been in clinical use for decades, specifically inhibits in vitro and in vivo the chemotactic activity of HMGB1 at nanomolar concentrations, at least in part by binding directly to both HMGB1 and CXCL12 and disrupting their heterocomplex. Importantly, Diflunisal does not inhibit TLR4-dependent responses. Our findings clarify the mode of action of Diflunisal, and open the way to the rational design of functionally specific anti-inflammatory drugs.

scholarly journals PARG Suppresses Tumorigenesis and Downregulates Genes Controlling Angiogenesis, Inflammatory Response, and Immune Cell Recruitment

2022 ◽  
Author(s):  
Sarah Johnson ◽  
Yaroslava Karpova ◽  
Danping Guo ◽  
Atreyi Ghatak ◽  
Dmitriy A. Markov ◽  
...  
Keyword(s):  
Immune Cell ◽  
Critical Role ◽  
Tumor Growth Inhibition ◽  
Rna Seq ◽  
Cell Recruitment ◽  
Tumor Onset ◽  
Tumor Tissues ◽  
Immune Cell Recruitment

Abstract Chemokines are highly expressed in tumor microenvironment and play a critical role in all aspects of tumorigenesis, including the recruitment of tumor-promoting immune cells, activation of cancer-associated fibroblasts, angiogenesis, metastasis, and growth. Poly(ADP-ribose) polymerase (PARP) is a multi-target transcription regulator with high levels of poly(ADP-ribose) (pADPr) being reported in a variety of cancers. Furthermore, poly(ADP-ribose) glycohydrolase (PARG), an enzyme that degrades pADPr, has been reported to be downregulated in tumor tissues with abnormally high levels of pADPr. In conjunction to this, we have recently reported that the reduction of pADPr, by either pharmacological inhibition of PARP or PARG’s overexpression, disrupts renal carcinoma cell malignancy in vitro. Here, we use 3T3 mouse embryonic fibroblasts, a universal model for malignant transformation, to follow the effect of PARG upregulation on cells’ tumorigenicity in vivo. We found that the overexpression of PARG in mouse allografts produces significantly smaller tumors with a delay in tumor onset. As downregulation of PARG has also been implicated in promoting the activation of pro-inflammatory genes, we also followed the gene expression profile of PARG-overexpressing 3T3 cells using RNA-seq approach and observed that chemokine transcripts are significantly reduced in those cells. Our data suggest that the upregulation of PARG may be potentially useful for the tumor growth inhibition in cancer treatment and as anti-inflammatory intervention.

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