Posts Tagged ‘German Cancer Research Center’

Reporter: Aviva Lev-Ari, PhD, RN




Trypanosoma cruzi Trans-Sialidase Initiates a Program Independent of the Transcription Factors RORγt and Ahr that Leads to IL-17 Production by Activated B Cells

Researchers identified B cells as a major source of rapid, innate-like production of interleukin 17 (IL-17) in vivo in response to infection with Trypanosoma cruzi. IL-17+ B cells had a plasmablast phenotype, outnumbered cells of the TH17 subset of helper T cells and were required for an optimal response to this pathogen. [Nat Immunol] Abstract

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Autoimmune Pancreatitis in MRL/Mp Mice Is a T Cell-Mediated Disease Responsive to Cyclosporine A and Rapamycin Treatment

The authors report that blockage of CTLA-4 in MRL/Mp mice suppressed regulatory T cell function and raised the effector T cell response with subsequent histomorphological organ destruction, indicating that autoimmune pancreatitis is a T cell-driven disease. Using an established histopathological score, they found that dexamethasone, cyclosporine A and rapamycin, but less so azathioprine, reduced pancreatic damage. [Gut] Abstract

Excessive Th1 Responses Due to the Absence of TGF-β Signaling Cause Autoimmune Diabetes and Dysregulated Treg Cell Homeostasis

TGF-β signaling in T cells is critical for peripheral T-cell tolerance by regulating effector CD4+ T helper (Th) cell differentiation. However, it is still controversial to what extent TGF-β signaling in Foxp3+ regulatory T (Treg) cells contributes to immune homeostasis. Researchers showed that abrogation of TGF-β signaling in thymic T cells led to rapid type 1 diabetes development in NOD mice transgenic for the BDC2.5 T-cell receptor. [Proc Natl Acad Sci USA] Abstract

Inhibition of PDE4B Suppresses Inflammation by Increasing Expression of the Deubiquitinase CYLD

The deubiquitinase CYLD acts as a key negative regulator to tightly control overactive inflammation. Most anti-inflammatory strategies have focused on directly targeting the positive regulator, which often results in significant side effects such as suppression of the host defense response. Researchers showed that inhibition of phosphodiesterase 4B (PDE4B) markedly enhances upregulation of CYLD expression in response to bacteria, thereby suggesting that PDE4B acts as a negative regulator for CYLD. [Nat Commun] Abstract | Press Release

Regulatory T Cells Prevent Plaque Disruption in Apolipoprotein E-Knockout Mice

Investigators report that adoptive transfer of regulatory T cells dose-dependently changed plaque composition to a stable plaque phenotype and lowered the incidence of plaque disruption in apolipoprotein E-knockout mice. The major mechanisms involved reduced expression of inflammatory cytokines and matrix metalloproteinase (MMP)-2 and MMP-9, and enhanced expression of P4Hα1 in the carotid plaque. [Int J Cardiol] Abstract

GARP-TGF-β Complexes Negatively Regulate Regulatory T Cell Development and Maintenance of Peripheral CD4+ T Cells In Vivo

Researchers address the role of Glycoprotein A Repetitions Predominant (GARP) in regulating regulatory T cells and conventional T cell development and immune suppression in vivo using a transgenic mouse expressing GARP on all T cells. They found that, despite forced expression of GARP on all T cells, stimulation through the TCR was required for efficient localization of GARP to the cell surface. [J Immunol] Abstract

Fine-Tuning of Regulatory T Cell Function: The Role of Calcium Signals and Naive Regulatory T Cells for Regulatory T Cell Deficiency in Multiple Sclerosis

As regulatory T cells (Tregs) counteract the sustained elevation of intracellular calcium, which is indispensable for full activation of conventional T cells (Tcons), the authors hypothesized that interference with this pathway might prompt multiple sclerosis-related Treg dysfunction. Using single-cell live imaging, they observed that Tregs rapidly reduce Ca2+ influx and downstream signals in Tcons upon cell contact, yet differ in their potency to efficiently suppress several target cells at the same time. [J Immunol] Abstract

Systems Model of T Cell Receptor Proximal Signaling Reveals Emergent Ultrasensitivity

Researchers used a systems model to show that signaling architecture produces emergent ultrasensitivity resulting in switch-like responses at the scale of individual T cell antigen receptors. Importantly, this switch-like response is an emergent property, so that removal of multiple immunoreceptor tyrosine-based activation motifs, sequential phosphorylation, or differential affinities abolishes the switch. [PLoS Comput Biol]

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Decreased Regulatory T-Cells and CD4+/CD8+ Ratio Correlate with Disease Onset and Progression in Patients with Generalized Vitiligo

Scientists evaluated CD4+/CD8+ ratio and CD4+CD25hiFoxP3+ regulatory T cells (Tregs) in Generalized Vitiligo (GV) patients with reference to their effect on disease onset and progression. Flow cytometry was used for determination of CD4+/CD8+ ratio and Tregs in 82 patients and 50 controls. CD8+ T-cell counts were significantly higher in GV patients as compared to controls. [Pigment Cell Melanoma Res] Abstract

Sex Bias in Experimental Immune-Mediated, Drug-Induced Liver Injury in BALB/c Mice: Suggested Roles for Tregs, Estrogen, and IL-6

Immune regulation by CD4+CD25+FoxP3+ regulatory T-cells (Tregs) and 17β-estradiol is crucial in the pathogenesis of sex bias in cancer and autoimmunity. Therefore, researchers investigated their role in a mouse model of immune-mediated drug-induced liver injury. [PLoS One] Full Article

The Hedgehog Receptor Patched1 in T Cells Is Dispensable for Adaptive Immunity in Mice

Hedgehog (Hh) signaling modulates T cell development and function but its exact role remains a matter of debate. To further address this issue, researchers made use of conditional knock-out mice in which the Hh receptor Patched1 is inactivated in the T cell lineage. [PLoS One] Full Article



Modulating T Regulatory Cells in Cancer: How Close Are We?

The authors provide a historical perspective of the discovery of regulatory T cells (Tregs), followed by a summary of the existing literature on the role of Tregs in malignancy. [Immunol Cell Biol] Abstract

Importance of Reverse Signaling of the TNF Superfamily in Immune Regulation

F-related ligands (with the exception of lymphotoxin-α) are synthesized as type II transmembrane proteins, though many of them also have soluble forms. An increasing number of publications report that these ‘ligands’ behave as receptors, activating intracellular signaling pathways when interacting with cognate ‘receptors’ or agonistic antibodies. [Expert Rev Clin Immunol] Abstract

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Immunotherapies against Cancer: German Cancer Research Center to Broaden Strategic Alliance with Bayer HealthCare

The German Cancer Research Center and Bayer HealthCare will extend their successful strategic research alliance in search of novel cancer therapeutics by focusing their activities also on the field of immunotherapy. [German Cancer Research Center] Press Release

Pitt Team Gets $5 Million National Institutes of Health Grant to Make Vaccine Component that Stimulates TB-Fighting T-Cells

Researchers at the University of Pittsburgh School of Medicine have received a $5 million federal grant to develop a vaccine ingredient that can generate the type of immune response needed to protect against tuberculosis (TB) infection. [UPMC/University of Pittsburgh Schools of the Health Sciences] Press Release

T Cell Biology Pioneer Allison Wins First AACR Honor for Cancer Immunology

The scientist whose discoveries led to the first drug approved for metastatic melanoma by “treating the immune system, not the cancer,” also is the first to receive the AACR-CRI Lloyd J. Old Award in Cancer Immunology. James Allison, Ph.D., professor and chair of The University of Texas MD Anderson Cancer Center Department of Immunology, was honored at the AACR Annual Meeting 2013 in Washington, D.C. [The University of Texas MD Anderson Cancer Center] Press Release

Immune Therapy from Austria Receives Orphan Drug Designation from European Medicines Agency

The European Medicines Agency recently awarded the Austrian biotech company Activartis an Orphan Drug Designation for its innovative Cancer Immune Therapy AV0113. The Orphan Drug Designation applies specifically to the use of AV0113 for the treatment of glioma, a type of brain tumor, which afflicts around one in 10.000 people in the EU. [Activartis Biotech GmbH] Press Release

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October 23-25, 2013

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Head and Neck Cancer Studies Suggest Alternative Markers More Prognostically Useful than HPV DNA Testing

Reporter: Aviva Lev-Ari, PhD, RN

September 18, 2012

NEW YORK (GenomeWeb News) – The presence or absence of human papillomavirus DNA on its own in an individual’s head or neck cancer does not provide enough information to help predict a patient’s survival, according to a pair of new papers in the journal Cancer Research.

Two research teams — headed by investigators at Brown University and Heidelberg University, respectively — looked at the reliability of using PCR-based HPV testing to determine which head and neck squamous cell carcinomas were HPV-related and, thus, more apt to respond to treatment.

Previous studies have shown that individuals with HPV-associated head and neck cancers tend to have more favorable outcomes than individuals whose head and neck cancers that are not related to HPV infection.

“Everybody who has studied it has shown that people with virally associated disease do better,” Brown University pathology researcher Karl Kelsey, a senior author on one of the new studies, explained in a statement.

“There are now clinical trials underway to determine if they should be treated differently,” he added. “The problem is that you need to appropriately diagnose virally related disease, and our data suggests that people need to take a close look at that.”

For their part, Kelsey and his co-authors from the US and Germany assessed the utility of testing for the presence of HPV by various means in individuals with head and neck cancer. This included PCR-based tests for HPV DNA in the tumor itself, tests aimed at detecting infection-associated antibodies in an individual’s blood, and tests for elevated levels of an HPV-related tumor suppressor protein.

For 488 individuals with HNSCC, researchers did blood-based testing for antibodies targeting HPV16 in general, as well as testing for antibodies that target the viral proteins E6 and E7.

For a subset of patients, the team assessed the tumors themselves for the presence of HPV DNA and/or for elevated levels of the host tumor suppressor protein p16.

Based on patterns in the samples, the group determined that the presence of viral E6 and E7 proteins in the blood was linked to increased survival for individuals with an oropharyngeal form of HNSCC, which affects part of the throat known as the oropharynx.

A positive test for HPV DNA alone was not significantly linked to head and neck cancer outcomes. On the other hand, when found in combination with E6 and E7 expression, a positive HPV16 test did coincide with improved oropharyngeal cancer outcomes.

Likewise, elevated levels of p16 in a tumor were not especially informative on their own, though they did correspond to better oropharyngeal cancer survival when found together with positive blood tests for E6 and E7.

Based on these findings, Kelsey and his team concluded that “[a] stronger association of HPV presence with prognosis (assessed by all-cause survival) is observed when ‘HPV-associated’ HNSCC is defined using tumor status (HPV DNA or P16) and HPV E6/E7 serology in combination rather [than] using tumor HPV status alone.”

In a second study, meanwhile, a German group that focused on the oropharyngeal form of the disease found its own evidence arguing against the use of HPV DNA as a solo marker for HPV-associated head and neck cancer.

For that analysis, researchers assessed 199 fresh-frozen oropharyngeal squamous cell carcinoma samples, testing the tumors for HPV DNA and p16. They also considered the viral load in the tumors and looked for gene expression profiles resembling those described in cervical carcinoma — another cancer associated with HPV infection.

Again, the presence of HPV DNA appeared to be a poor indicator of HPV-associated cancers or predictor of cancer outcomes. Whereas nearly half of the tumors tested positive for HPV16 DNA, just 16 percent and 20 percent had high viral loads and cervical cancer-like expression profiles, respectively.

The researchers found that a subset of HPV DNA-positive tumors with high viral load or HPV-associated expression patterns belonged to individuals with better outcomes. In particular, they found that cervical cancer-like expression profiles in oropharyngeal tumors coincided with the most favorable outcomes, while high viral load in the tumors came a close second.

“We showed that high viral load and a cancer-specific pattern of viral gene expression are most suited to identify patients with HPV-driven tumors among patients with oropharyngeal cancer,” Dana Holzinger, that study’s corresponding author, said in a statement.

“Once standardized assays for these markers, applicable in routine clinical laboratories, are established, they will allow precise identification of patients with oropharyngeal cancer with or without HPV-driven cancers and, thus, will influence prognosis and potentially treatment decisions,” added Holzinger, who is affiliated with the German Cancer Research Center and Heidelberg University.

In a commentary article online today in Cancer Research, Eduardo Méndez, a head and neck surgery specialist with the University of Washington and Fred Hutchinson Cancer Research Centerdiscussed the significance of the two studies and their potential impact on oropharyngeal squamous cell carcinoma prognoses and treatment.

But he also cautioned that more research is needed to understand whether the patterns described in the new studies hold in other populations and to tease apart the prognostic importance of HPV infection in relation to additional prognostic markers.



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