ICOS-Positive Regulatory T Cells in Hepatocellular Carcinoma: The Perspective from Digital Pathology Analysis.

Introduction: Inducible co-stimulator (ICOS), an important co-stimulatory receptor on effector T cells (Teffs), may also contribute to tumor growth due to its high expression on regulatory T cells (Tregs). This study explored the clinical significance of ICOS-expressing Tregs in hepatocellular carcinoma (HCC).

Methods: Tumor tissues from HCC patients who received curative hepatectomy were obtained at a referral center.

Downregulation of Manic fringe impedes angiogenesis and cell migration of renal carcinoma.

Clear cell renal cell carcinoma (ccRCC) is a highly angiogenic cancer. Manic fringe (MFng) is elevated in ccRCC compared to the normal kidney. However, its role in ccRCC tumour angiogenesis remains elusive.

An Antibody Targeting ICOS Increases Intratumoral Cytotoxic to Regulatory T-cell Ratio and Induces Tumor Regression.

The immunosuppressive tumor microenvironment constitutes a significant hurdle to immune checkpoint inhibitor responses. Both soluble factors and specialized immune cells, such as regulatory T cells (Treg), are key components of active intratumoral immunosuppression. Inducible costimulatory receptor (ICOS) can be highly expressed in the tumor microenvironment, especially on immunosuppressive Treg, suggesting that it represents a relevant target for preferential depletion of these cells.

Optoacoustic Detection of Early Therapy-Induced Tumor Cell Death Using a Targeted Imaging Agent.

The development of new treatments and their deployment in the clinic may be assisted by imaging methods that allow an early assessment of treatment response in individual patients. The C2A domain of Synaptotagmin-I (C2Am), which binds to the phosphatidylserine (PS) exposed by apoptotic and necrotic cells, has been developed as an imaging probe for detecting cell death. Multispectral optoacoustic tomography (MSOT) is a real-time and clinically applicable imaging modality that was used here with a near infrared (NIR) fluorophore-labeled C2Am to image tumor cell death in mice treated with a TNF-related apoptosis-inducing ligand receptor 2 (TRAILR2) agonist and with 5-fluorouracil (5-FU).

Rational Selection of Syngeneic Preclinical Tumor Models for Immunotherapeutic Drug Discovery.

Murine syngeneic tumor models are critical to novel immuno-based therapy development, but the molecular and immunologic features of these models are still not clearly defined. The translational relevance of differences between the models is not fully understood, impeding appropriate preclinical model selection for target validation, and ultimately hindering drug development. Across a panel of commonly used murine syngeneic tumor models, we showed variable responsiveness to immunotherapies.

Characterization and application of two RANK-specific antibodies with different biological activities.

Antibodies play an important role in therapy and investigative biomedical research. The TNF-family member Receptor Activator of NF-κB (RANK) is known for its role in bone homeostasis and is increasingly recognized as a central player in immune regulation and epithelial cell activation. However, the study of RANK biology has been hampered by missing or insufficient characterization of high affinity tools that recognize RANK.

Regulation of the anti-tumour immune response by cancer-associated fibroblasts.

The microenvironment of established tumours is often immunosuppressed, and this allows tumours to grow and disseminate without being eliminated by the patient's immune system. The recent FDA approval of immunotherapies such as ipilimumab and sipuleucel-T that directly activate the adaptive and innate immune responses has triggered interest in developing other novel anti-cancer approaches that modulate the immune system. Understanding how the different constituents of the tumour microenvironment influence the immune system is thus crucial and is expected to generate a plethora of factors that can be targeted to boost immunity and trigger long lasting anti-tumour efficacy.

Regulation of CXCR4 by the Notch ligand delta-like 4 in endothelial cells.

Gene-targeting studies have shown that Delta-like 4 (Dll4) is required for normal embryonic vascular remodeling, but the mechanisms underlying Dll4 regulatory functions are not well defined. We generated primary human umbilical vascular endothelial cells that express Dll4 protein to study Dll4 function and previously showed that Dll4 down-regulates vascular endothelial growth factor (VEGF) receptor 2 and NRP1 expression and inhibits VEGF function. We now report that expression of Dll4 in endothelial cells inhibited attachment and migration to stromal-derived growth factor 1 (SDF1) chemokine.

Regulation of angiogenesis by homotypic and heterotypic notch signalling in endothelial cells and pericytes: from basic research to potential therapies.

The notch-signalling pathway regulates cell fate and differentiation through cell-cell communication. In recent years, several in vitro and in vivo studies have demonstrated that notch-signalling functions as a negative feedback mechanism downstream of the VEGF-signalling pathway that acts to finely shape the vascular network. Notch activation by the Jagged-1 and Delta-like 4 ligands regulates different steps of blood vessel development ranging from proliferation and survival of endothelial cells, to vessel branching and arterial-venous differentiation.

Delta-like 4 Notch ligand regulates tumor angiogenesis, improves tumor vascular function, and promotes tumor growth in vivo.

The vascular endothelial growth factor (VEGF) plays a key role in tumor angiogenesis. However, clinical trials targeting the VEGF pathway are often ineffective, suggesting that other factors/pathways are also important in tumor angiogenesis. We have previously shown that the Notch ligand Delta-like 4 (DLL4) is up-regulated in tumor vasculature.

Anti-Dll4 therapy: can we block tumour growth by increasing angiogenesis?

Since the early 1970s, the dogma postulating that blocking tumour angiogenesis can inhibit tumour growth has been accepted widely and has resulted in the generation of a variety of successful anti-angiogenic therapies. More recently, new signalling pathways, such as the Dll4-Notch signalling pathway, have been shown to regulate angiogenesis during development. In pathological conditions, such as cancer, Dll4 is up-regulated strongly in the tumour vasculature.

Regulation of multiple angiogenic pathways by Dll4 and Notch in human umbilical vein endothelial cells.

The Notch ligand, Dll4, is essential for angiogenesis during embryonic vascular development and is involved in tumour angiogenesis. Several recent publications demonstrated that blockade of Dll4 signalling inhibits tumour growth, suggesting that it may constitute a good candidate for anti-cancer therapy. In order to understand the role of Dll4 at the cellular level, we performed an analysis of Dll4-regulated genes in HUVECs.

A conserved mechanism for steroid receptor translocation to the plasma membrane.

Multiple steroid receptors (SR) have been proposed to localize to the plasma membrane. Some structural elements for membrane translocation of the estrogen receptor alpha (ER alpha) have been described, but the mechanisms relevant to other steroid receptors are entirely unknown. Here, we identify a highly conserved 9 amino acid motif in the ligand binding domains (E domains) of human/mouse ER alpha and ER beta, progesterone receptors A and B, and the androgen receptor.

Hypoxia-regulated differentiation: let's step it up a Notch.

Although hypoxia is widely associated with adult pathologies such as cancer, it is also a physiological process that regulates cell differentiation during organogenesis. In an attempt to characterize the molecular mechanisms that are involved in hypoxia-regulated cell fate, a recent publication by Gustafsson and colleagues elegantly demonstrated that hypoxia blocks cell differentiation through the regulation of Notch signalling. This study showed that hypoxia-inducible factor (HIF)-1alpha interacts and acts in synergy with the Notch intracellular domain (NIC) and subsequently activates transcription of Notch targets.

Cell-autonomous notch signaling regulates endothelial cell branching and proliferation during vascular tubulogenesis.

The requirement for notch signaling during vascular development is well-documented but poorly understood. Embryonic and adult endothelial cells (EC) express notch and notch ligands; however, the necessity for cell-autonomous notch signaling during angiogenesis has not been determined. During angiogenesis, EC display plasticity, whereby a subset of previously quiescent cells loses polarity and becomes migratory.

Diffusion limits of an in vitro thick prevascularized tissue.

Although tissue engineering promises to replace or restore lost function to nearly every tissue in the body, successful applications are currently limited to tissue less than 2 mm in thickness. in vivo capillary networks deliver oxygen and nutrients to thicker (> 2 mm) tissues, suggesting that introduction of a preformed in vitro vascular network may be a useful strategy for engineered tissues. This article describes a system for generating capillary-like networks within a thick fibrin matrix.

VEGF(121) and VEGF(165) regulate blood vessel diameter through vascular endothelial growth factor receptor 2 in an in vitro angiogenesis model.

Vascular endothelial growth factor (VEGF) is essential for the induction of angiogenesis and drives both endothelial cell (EC) proliferation and migration. It has been suggested that VEGF also regulates vessel diameter, although this has not been tested explicitly. The two most abundant isoforms, VEGF(121) and VEGF(165), both signal through VEGF receptor 2 (VEGFR-2).