Immune Regulation News Volume 9.17 | May 12 2017

TOP STORY

Visualizing Dynamic Microvillar Search and Stabilization during Ligand Detection by T Cells

It has long been supposed that small microvilli on T cell surfaces are used as sensory organs to enable the search for peptide-loaded major histocompatibility complexes, but their strategy has not been amenable to study. Scientists used time-resolved lattice light-sheet microscopy and quantum dot–enabled synaptic contact mapping microscopy to show how microvilli on the surface of T cells search opposing cells and surfaces before and during antigen recognition. [Science] Full Article | Press Release

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Recruited Monocytes and Type 2 Immunity Promote Lung Regeneration following Pneumonectomy

To investigate the role of immune cells in lung regeneration, researchers used a unilateral pneumonectomy model that promotes the formation of new alveoli in the remaining lobes. Immunofluorescence and single-cell RNA sequencing found CD115⁺ and CCR2⁺ monocytes and M2-like macrophages accumulating in the lung during the peak of type 2 alveolar epithelial stem cell proliferation. [Cell Stem Cell] Abstract | Graphical Abstract

In Vivo Imaging Reveals a Tumor-Associated Macrophage–Mediated Resistance Pathway in Anti–PD-1 Therapy

Scientists demonstrated that in vivo blockade of Fcγ receptors before anti–programmed cell death protein 1 (aPD-1) monoclonal antibodies (mAb) administration substantially prolongs aPD-1 mAb binding to tumor-infiltrating CD8⁺ T cells and enhances immunotherapy-induced tumor regression in mice. [Sci Transl Med] Abstract

Potent Antitumor Activity of Interleukin-2-Fc Fusion Proteins Requires Fc-Mediated Depletion of Regulatory T-Cells

The authors describe a novel determinant of antitumor activity using fusion proteins consisting of IL-2 and the antibody fragment crystallizable (Fc) region. Generation of long-lived IL-2-Fc variants in which CD25 binding is abolished through mutation effectively prevented unwanted activation of CD25⁺ regulatory T-cells and resulted in strong expansion of CD25⁻ cytotoxic subsets. [Nat Commun] Full Article

Foxp3⁺ Regulatory T Cells Maintain the Bone Marrow Microenvironment for B Cell Lymphopoiesis

Investigators showed that B-cell lymphopoiesis was impaired in regulatory T cells (Treg)-depleted mice, yet this reduced B-cell lymphopoiesis was rescued by adoptive transfer of affected hematopoietic stem cell or bone marrow cells into Treg-competent recipients. B-cell reconstitution is abrogated in both syngeneic and allogeneic transplantation using Treg-depleted mice as recipients. Treg cells can control physiological IL-7 production that is indispensable for normal B-cell lymphopoiesis and is mainly sustained by a subpopulation of ICAM1⁺ perivascular stromal cells. [Nat Commun] Full Article

Na⁺ Influx via Orai1 Inhibits Intracellular ATP Induced mTORC2 Signaling to Disrupt CD4 T Cell Gene Expression and Differentiation

Scientists showed that α-SNAP hypomorph, hydrocephalos with hopping gait, Napa^hyh/hyh mice harbor significant defects in CD4 T cell gene expression and Foxp3 regulatory T cell (Treg) differentiation. TCR stimulation in the presence of monensin phenocopied the defects in Napa^hyh/hyh signaling and Treg differentiation, but not IL-2 expression. [eLife] Full Article

Essential Roles of SATB1 in Specifying T Lymphocyte Subsets

Investigators showed that, in post-selection thymocytes, a genome organizer, SATB1, activates genes for lineage-specifying factors, including ThPOK, Runx3, CD4, CD8, and Treg factor Foxp3, via regulating enhancers in these genes in a locus-specific manner. SATB1-deficient thymocytes were partially re-directed into inappropriate T lineages after both MHC class I- and II-mediated selection, and they failed to generate NKT and Treg subsets. Despite its essential role in activating enhancers for the gene encoding ThPOK in T cell receptor-signaled thymocytes, SATB1 becomes dispensable for maintaining ThPOK in CD4⁺ T cells. [Cell Rep] Full Article | Graphical Abstract

MSC-Derived Extracellular Vesicles Attenuate Immune Responses in Two Autoimmune Murine Models: Type 1 Diabetes and Uveoretinitis

Scientists investigated the therapeutic potential of mesenchymal stem/stromal cells (MSC)-derived extracellular vesicles (EVs) using established mouse models for autoimmune diseases affecting the pancreas and the eye: type 1 diabetes (T1D) and experimental autoimmune uveoretinitis (EAU). Their data demonstrated that MSC-derived EVs effectively prevent the onset of disease in both T1D and EAU. In addition, the mixed lymphocyte reaction assay with MSC-derived EVs indicated that EVs inhibit activation of antigen-presenting cells and suppress development of T helper 1 (Th1) and Th17 cells. [Stem Cell Reports] Full Article

B7-DC (PD-L2) Costimulation of CD4⁺ T-Helper 1 Response via RGMb

Researchers showed that recombinant K113S protein interacts with repulsive guidance molecule b (RGMb) with a similar affinity to wild-type B7-DC. K113S costimulated CD4⁺ T-cell responses via RGMb and promoted Th1 polarization. RGMb was expressed on the surface of naive mouse T cells, macrophages, neutrophils and dendritic cells. K113S/RGMb costimulation suppressed Th2-mediated asthma and ameliorates small airway inflammation and lung pathology in an experimental mouse model. [Mol Immunol] Abstract

C3d Regulates Immune Checkpoint Blockade and Enhances Antitumor Immunity

The authors report that free C3d, a fragment of the third component of complement, inside tumor cells — or associated with irradiated tumor cells and unattached to antigen — recruits, accelerates, and amplifies antitumor T cell responses, allowing immunity to reverse or even to prevent tumor growth. [JCI Insight] Abstract | Press Release

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Vaccine-Based Immunotherapeutic Approaches to Gliomas and Beyond

The authors review vaccination approaches investigated for the treatment of glioma. Several strategies have reached Phase III clinical trials, including vaccines targeting epidermal growth factor receptor variant III, and the use of either immunogenic peptides or tumor lysates to stimulate autologous dendritic cells. Other approaches in early phases of clinical development employ multipeptide vaccines such as IMA-950, cytomegalovirus-derived peptides, or tumor-derived peptides such as heat shock protein-96 peptide complexes and the Arg132His mutant form of isocitrate dehydrogenase. [‎Nat Rev Neurol] Abstract

Expanding Diversity and Common Goal of Regulatory T and B Cells. II: In Allergy, Malignancy, and Transplantation

Scientists review the significance of therapies based on regulatory cells in areas such as autoimmune diseases, allergy, malignancy, organ transplantation. [Arch Immunol Ther Exp (Warsz)] Full Article

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Kadmon to Present Clinical and Preclinical Data Highlighting the Role of ROCK2 Signaling in Immune System Function

Kadmon Holdings, Inc. announced the presentation of data from its completed Phase II clinical trial of KD025, the company’s oral Rho-associated coiled-coil kinase 2 (ROCK2) inhibitor, in patients with moderate to severe psoriasis, as well as new preclinical data demonstrating the importance of ROCK2 signaling in regulating the pro-inflammatory aspect of immune response. [Press release from Kadmon Holdings, Inc. discussing research to be presented at the American Association of Immunologists (AAI) Annual Meeting, Washington D.C.] Press Release

Genentech to Present New Data on Personalized Medicines and Cancer Immunotherapies at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting

Genentech announced new data on 20 approved and investigational medicines will be presented. More than 190 abstracts have been accepted, including two “late breakers” and 24 oral presentations. [Press release from Genentech discussing research to be presented at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago] Press Release

FDA Approves Merck’s KEYTRUDA^® (Pembrolizumab) as First-Line Combination Therapy with Pemetrexed and Carboplatin for Patients with Metastatic Nonsquamous Non-Small Cell Lung Cancer (NSCLC), Irrespective of PD-L1 Expression

Merck announced that the U.S. Food and Drug Administration (FDA) has approved KEYTRUDA^®, the company’s anti-PD-1 therapy, in combination with pemetrexed and carboplatin, a commonly used chemotherapy regimen, for the first-line treatment of metastatic nonsquamous NSCLC, irrespective of PD-L1 expression. [Merck Sharp & Dohme Corp.] Press Release

AstraZeneca’s Imfinzi (Durvalumab) Receives US FDA Accelerated Approval for Previously Treated Patients with Advanced Bladder Cancer

AstraZeneca and its global biologics research and development arm, MedImmune, announced that the US Food and Drug Administration (FDA) has granted accelerated approval to Imfinzi, a human monoclonal antibody that blocks PD-L1. Imfinzi is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy, or whose disease has progressed within 12 months of receiving platinum-containing chemotherapy before or after surgery. [AstraZeneca] Press Release

Selexis SA Opens New World-Class Laboratory Facility and Corporate Headquarters in Geneva, Switzerland

Selexis SA, announced the dedication of a new, state-of-the-art laboratory and corporate headquarters in Geneva, Switzerland. Selexis CEO and Chairman Igor Fisch, PhD, officially introduced the new space to a host of Swiss-based biotech and government dignitaries. [Selexis SA] Press Release

The Wistar Institute Appoints Daniel W. Kulp, Ph.D., as Associate Professor in the Vaccine Center and Translational Tumor Immunology Program

The Wistar Institute announced the appointment of Daniel W. Kulp, Ph.D., as associate professor in the Vaccine Center and the Translational Tumor Immunology Program. [The Wistar Institute] Press Release

China Cracks Down on Fake Data in Drug Trials

Those who submit faked clinical trial data might now go to jail — and in extreme circumstances, be executed — under a new interpretation of China’s criminal code. The policy shift is one of a handful of measures that China is implementing both to speed up its notoriously slow drug-approval process and to keep dangerous and ineffective drugs off the market. [Nature News] Editorial

The Secret War against Counterfeit Science

China is famous for knock-off DVDs, Louis Vuitton bags and Rolex watches. But counterfeit reagents aren’t on sale in busy public markets. They are sold through sophisticated websites, mixed in with legitimate supplies, and sourced and sold using a network of unwitting partners. [Nature News] Editorial

Science Publishers Try New Tack to Combat Unauthorized Paper Sharing

The unauthorized sharing of copyrighted research papers is on the rise, say analysts who track the publishing industry. Faced with this problem, science publishers seem to be changing tack in their approach to researchers who breach copyright. [Nature News] Editorial

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