Rejection of human cancer transplants by tolerant rats following treatment with allogeneic lymphoid cells

We generated a monoclonal antibody (MAb), designated LN-6, directed against human vimentin, which retains its immunoreactivity in B5-fixed, paraffin-embedded tissues. Like other anti-vimentin MAb, LN-6 was found to be reactive with a wide spectrum of human sarcomas and normal cells of mesenchymal derivation. However, unlike other similar reagents, LN-6 was unreactive with normal and malignant human lymphoid cells and therefore displays a more restricted immunoreactivity. Because of its ability to stain routinely processed pathological tissues and its marked reactivity with human sarcomas, LN-6 is a unique reagent for the immunohistochemical diagnosis of human cancer.

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Requirement for the SnoN Oncoprotein in Transforming Growth Factor β-Induced Oncogenic Transformation of Fibroblast Cells

Molecular and Cellular Biology ◽

10.1128/mcb.25.24.10731-10744.2005 ◽

2005 ◽

Vol 25 (24) ◽

pp. 10731-10744 ◽

Cited By ~ 35

Author(s):

Qingwei Zhu ◽

Sonia Pearson-White ◽

Kunxin Luo

Keyword(s):

Growth Factor ◽

Epithelial Cells ◽

Cancer Cells ◽

Transforming Growth Factor ◽

Human Cancer ◽

Transforming Growth Factor Β ◽

Lymphoid Cells ◽

Human Cancer Cells ◽

Inhibitory Site ◽

Transforming Activity

ABSTRACT Transforming growth factor β (TGF-β) was originally identified by virtue of its ability to induce transformation of the AKR-2B and NRK fibroblasts but was later found to be a potent inhibitor of the growth of epithelial, endothelial, and lymphoid cells. Although the growth-inhibitory pathway of TGF-β mediated by the Smad proteins is well studied, the signaling pathway leading to the transforming activity of TGF-β in fibroblasts is not well understood. Here we show that SnoN, a member of the Ski family of oncoproteins, is required for TGF-β-induced proliferation and transformation of AKR-2B and NRK fibroblasts. TGF-β induces upregulation of snoN expression in both epithelial cells and fibroblasts through a common Smad-dependent mechanism. However, a strong and prolonged activation of snoN transcription that lasts for 8 to 24 h is detected only in these two fibroblast lines. This prolonged induction is mediated by Smad2 and appears to play an important role in the transformation of both AKR-2B and NRK cells. Reduction of snoN expression by small interfering RNA or shortening of the duration of snoN induction by a pharmacological inhibitor impaired TGF-β-induced anchorage-independent growth of AKR-2B cells. Interestingly, Smad2 and Smad3 play opposite roles in regulating snoN expression in both fibroblasts and epithelial cells. The Smad2/Smad4 complex activates snoN transcription by direct binding to the TGF-β-responsive element in the snoN promoter, while the Smad3/Smad4 complex inhibits it through a novel Smad inhibitory site. Mutations of Smad4 that render it defective in heterodimerization with Smad3, which are found in many human cancers, convert the activity of Smad3 on the snoN promoter from inhibitory to stimulatory, resulting in increased snoN expression in cancer cells. Thus, we demonstrate a novel role of SnoN in the transforming activity of TGF-β in fibroblasts and also uncovered a mechanism for the elevated SnoN expression in some human cancer cells.

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P01.17 Tim-3/Galectin-9 pathway controls the ability of malignant cells to escape host immune surveillance. Regulatory mechanisms and therapeutic targets

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-itoc7.30 ◽

2020 ◽

Vol 8 (Suppl 2) ◽

pp. A16.2-A17

Author(s):

VV Sumbayev ◽

IM Yasinska ◽

SS Sakhnevych ◽

E Fasler-Kan ◽

BF Gibbs

Keyword(s):

Cancer Cells ◽

Human Cancer ◽

Immune Surveillance ◽

Malignant Tumour ◽

Lymphoid Cells ◽

Human Cancer Cells ◽

Anti Cancer ◽

Biochemical Mechanisms ◽

Host Immune Surveillance ◽

Cancer Activity

BackgroundHuman cancer cells implement a variety of biochemical mechanisms which allow them to escape host immune surveillance resulting in disease progression. We have reported that the immune receptor Tim-3 and its natural ligand and possible trafficker galectin-9 determine the capability of human acute myeloid leukemia (AML) cells to evade cytotoxic immune attack.1 Our further studies demonstrated that breast, colorectal and other human solid malignant tumour cells display high activity of this pathway2 which can also be used for immune evasion. It is, however, important to understand the mechanisms which regulate the biochemical activity of Tim-3/galectin-9 pathway and expression of its components as well as the molecular basis of its capability to impair anti-cancer activity of cytotoxic lymphoid cells.Materials and MethodsIn this study we used human cancer and non-malignant cell lines as well as primary human malignant tumour samples. We also used primary human T cells and natural killer (NK) cells. Western blot analysis, ELISA, quantitative real-time PCR, on-cell Western, immunohistochemistry, flow cytometry and biochemical assays were used as key instrumentals to conduct measurements.ResultsWe found that galectin-9 is used by human cancer cells to escape host immune surveillance. Cancer cells use various biochemical pathways to overexpress galectin-9. Regardless the biochemical background, transforming growth factor-beta (TGF-β) and transcription factor Smad-3 play crucial role in galectin-9 expression in human cancer cells. We identified the key receptors through which galectin-9 can then trigger killing of cytotoxic T lymphocytes and impairing of anti-cancer activity of natural killer cells.ConclusionsIn this work, we report the biochemical mechanisms underlying overexpression of galectin-9 in human malignant tumour cells and its differential effects on human cytotoxic lymphoid cells.ReferencesGonçalves Silva I, Yasinska IM, Sakhnevych SS, et al. EBioMedicine 2017; 22: 44–57.Yasinska IM, et al. Front Immunol 2019;10:1594.Disclosure InformationV.V. Sumbayev: None. I.M. Yasinska: None. S.S. Sakhnevych: None. E. Fasler-Kan: None. B.F. Gibbs: None.

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Osteopontin: A Key Regulator of Tumor Progression and Immunomodulation

Cancers ◽

10.3390/cancers12113379 ◽

2020 ◽

Vol 12 (11) ◽

pp. 3379

Author(s):

Hannah R. Moorman ◽

Dakota Poschel ◽

John D. Klement ◽

Chunwan Lu ◽

Priscilla S. Redd ◽

...

Keyword(s):

T Cell ◽

Tumor Microenvironment ◽

Cancer Patients ◽

T Cell Activation ◽

Cell Activation ◽

Human Cancer ◽

Macrophage Polarization ◽

Elevated Serum ◽

Lymphoid Cells ◽

Wide Range

OPN is a multifunctional phosphoglycoprotein expressed in a wide range of cells, including osteoclasts, osteoblasts, neurons, epithelial cells, T, B, NK, NK T, myeloid, and innate lymphoid cells. OPN plays an important role in diverse biological processes and is implicated in multiple diseases such as cardiovascular, diabetes, kidney, proinflammatory, fibrosis, nephrolithiasis, wound healing, and cancer. In cancer patients, overexpressed OPN is often detected in the tumor microenvironment and elevated serum OPN level is correlated with poor prognosis. Initially identified in activated T cells and termed as early T cell activation gene, OPN links innate cells to adaptive cells in immune response to infection and cancer. Recent single cell RNA sequencing revealed that OPN is primarily expressed in tumor cells and tumor-infiltrating myeloid cells in human cancer patients. Emerging experimental data reveal a key role of OPN is tumor immune evasion through regulating macrophage polarization, recruitment, and inhibition of T cell activation in the tumor microenvironment. Therefore, in addition to its well-established direct tumor cell promotion function, OPN also acts as an immune checkpoint to negatively regulate T cell activation. The OPN protein level is highly elevated in peripheral blood of human cancer patients. OPN blockade immunotherapy with OPN neutralization monoclonal antibodies (mAbs) thus represents an attractive approach in human cancer immunotherapy.

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Lymphoproliferative disorders (LPD) involving lungs: T and B cell subsets within pulmonary infiltrates and in peripheral blood

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s042482010011338x ◽

1984 ◽

Vol 42 ◽

pp. 700-701

Author(s):

Irene Stachura ◽

Milton H. Dalbow ◽

Michael J. Niemiec ◽

Matias Pardo ◽

Gurmukh Singh ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Lymphoproliferative Disorders ◽

Mixed Population ◽

Lymphoid Cells ◽

Lymphomatoid Granulomatosis ◽

Cell Type ◽

Cell Surface Antigens ◽

Pulmonary Infiltrates ◽

B Cell Subsets

Lymphoid cells were analyzed within pulmonary infiltrates of six patients with lymphoproliferative disorders involving lungs by immunofluorescence and immunoperoxidase techniques utilizing monoclonal antibodies to cell surface antigens T11 (total T), T4 (inducer/helper T), T8 (cytotoxic/suppressor T) and B1 (B cells) and the antisera against heavy (G,A,M) and light (kappa, lambda) immunoglobulin chains. Three patients had pseudolymphoma, two patients had lymphoma and one patient had lymphomatoid granulomatosis.A mixed population of cells was present in tissue infiltrates from the three patients with pseudolymphoma, IgM-kappa producing cells constituted the main B cell type in one patient. In two patients with lymphoma pattern the infiltrates were composed exclusively of T4+ cells and IgG-lambda B cells predominated slightly in the patient with lymphomatoid granulomatosis.

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Two isoprenylated flavonoids from Dorstenia psilurus activate AMPK, stimulate glucose uptake, inhibit glucose production and lower glycemia

Biochemical Journal ◽

10.1042/bcj20190326 ◽

2019 ◽

Vol 476 (24) ◽

pp. 3687-3704 ◽

Cited By ~ 2

Author(s):

Aphrodite T. Choumessi ◽

Manuel Johanns ◽

Claire Beaufay ◽

Marie-France Herent ◽

Vincent Stroobant ◽

...

Keyword(s):

Glucose Uptake ◽

Human Cancer ◽

Glucose Production ◽

Liver Mitochondria ◽

New Drugs ◽

Structural Isomer ◽

Rat Liver Mitochondria ◽

Ionization Mass ◽

Ampk Activation ◽

Starting Point

Root extracts of a Cameroon medicinal plant, Dorstenia psilurus, were purified by screening for AMP-activated protein kinase (AMPK) activation in incubated mouse embryo fibroblasts (MEFs). Two isoprenylated flavones that activated AMPK were isolated. Compound 1 was identified as artelasticin by high-resolution electrospray ionization mass spectrometry and 2D-NMR while its structural isomer, compound 2, was isolated for the first time and differed only by the position of one double bond on one isoprenyl substituent. Treatment of MEFs with purified compound 1 or compound 2 led to rapid and robust AMPK activation at low micromolar concentrations and increased the intracellular AMP:ATP ratio. In oxygen consumption experiments on isolated rat liver mitochondria, compound 1 and compound 2 inhibited complex II of the electron transport chain and in freeze–thawed mitochondria succinate dehydrogenase was inhibited. In incubated rat skeletal muscles, both compounds activated AMPK and stimulated glucose uptake. Moreover, these effects were lost in muscles pre-incubated with AMPK inhibitor SBI-0206965, suggesting AMPK dependency. Incubation of mouse hepatocytes with compound 1 or compound 2 led to AMPK activation, but glucose production was decreased in hepatocytes from both wild-type and AMPKβ1−/− mice, suggesting that this effect was not AMPK-dependent. However, when administered intraperitoneally to high-fat diet-induced insulin-resistant mice, compound 1 and compound 2 had blood glucose-lowering effects. In addition, compound 1 and compound 2 reduced the viability of several human cancer cells in culture. The flavonoids we have identified could be a starting point for the development of new drugs to treat type 2 diabetes.

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