Immune Regulation News Volume 9.20 | June 2 2017

TOP STORY

Lymphatic Endothelial S1P Promotes Mitochondrial Function and Survival in Naive T Cells

Researchers demonstrated that lymphatic endothelial cells support the survival of T cells by secreting sphingosine 1-phosphate (S1P) via the transporter SPNS2, that this S1P signals through S1P₁ receptor (S1P₁R) on T cells, and that the requirement for S1P₁R is independent of the established role of the receptor in guiding exit from lymph nodes. [Nature] Abstract

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Post-Translational Control of T Cell Development by the ESCRT Protein CHMP5

The authors identified the endosomal-sorting-complex-required-for-transport (ESCRT) protein CHMP5, known to be required for the formation of multivesicular bodies, as a key sensor of thresholds for signaling via the T cell antigen receptor that was essential for T cell development. [Nat Immunol] Abstract

T Cell Expression of AhR Inhibits the Maintenance of pTreg Cells in the GI Tract in Acute GvHD

The Aryl-hydrocarbon-receptor (AhR) is a ligand-activated transcription factor that affects the function and development of immune cells. Scientists showed that recipient mice receiving AhR^-/- T cells had improved survival and decreased acute graft versus host disease (aGvHD) in two different murine allogeneic bone marrow transplant models (BMT). They also showed that CD4⁺ T cells lacking AhR demonstrated reduced accumulation in secondary lymphoid tissue due to low levels of proliferation four days after BMT. [Blood] Abstract

Glucose Represses Dendritic Cell-Induced T Cell Responses

Investigators showed a contrasting function for glucose in dendritic cells (DCs), as glucose represses the proinflammatory output of LPS-stimulated DCs and inhibits DC-induced T-cell responses. A glucose-sensitive signal transduction circuit involving the mTOR complex 1, HIF1α and inducible nitric oxide synthase coordinates DC metabolism and function to limit DC-stimulated T-cell responses. [Nat Commun] Full Article | Press Release

JunB Is Essential for IL-23-Dependent Pathogenicity of T_h17 Cells

Researchers showed that the AP-1 transcription factor JunB is critical for T_H17 pathogenicity. JunB, which is induced by interleukin (IL)-6, is essential for expression of RORγt and IL-23 receptor by facilitating DNA binding of BATF at the Rorc locus in IL-23-dependent pathogenic T_H17 cells, but not in TGF-β1-dependent non-pathogenic T_H17 cells. [Nat Commun] Full Article | Press Release

NOX2-Dependent ATM Kinase Activation Dictates Pro-Inflammatory Macrophage Phenotype and Improves Effectiveness to Radiation Therapy

Scientists showed that ionizing radiation induces the expression of interferon regulatory factor 5 (IRF5) promoting thus macrophage activation toward a pro-inflammatory phenotype. They revealed that the activation of the ataxia telangiectasia mutated (ATM) kinase is required for ionizing radiation-elicited macrophage activation, but also for macrophage reprogramming after treatments with γ-interferon, lipopolysaccharide or chemotherapeutic agent (such as cisplatin), underscoring the fact that the kinase ATM plays a central role during macrophage phenotypic switching toward a pro-inflammatory phenotype through the regulation of mRNA level and post-translational modifications of IRF5. [Cell Death Differ] Abstract

A TLR3-Specific Adjuvant Relieves Innate Resistance to PD-L1 Blockade without Cytokine Toxicity in Tumor Vaccine Immunotherapy

The authors have developed a safe vaccine adjuvant for cancer that effectively implements anti-programmed cell death-1/ligand 1 (PD-L1) therapy. Co-administration of ARNAX with a tumor-associated antigen facilitated tumor regression in mouse models, and in combination with an anti-PD-L1 antibody, activated tumor-specific cytotoxic T lymphocytes (CTLs) in lymphoid tissues, enhanced CTL infiltration, and overcame anti-PD-1 resistance without cytokinemia. [Cell Rep] Full Article | Graphical Abstract

Interferon-γ Derived from Cytotoxic Lymphocytes Directly Enhances their Motility and Cytotoxicity

Scientists investigated the mechanisms by which interferon gamma (IFNγ) mediates CD8 T-cell cytotoxic function. They showed that in vivo, antigen-specific CD8 T cells that produce INFγ are necessary to effect rejection of skin grafts expressing OVA as a transgene in keratinocytes. The ability of CD8 T cells to produce IFNγ enhanced their ability to migrate to the site of antigen-presenting skin cells. [Cell Death Dis] Full Article

Antibody Blockade of CLEC12A Delays EAE Onset and Attenuates Disease Severity by Impairing Myeloid Cell CNS Infiltration and Restoring Positive Immunity

Investigators identified functions of one C-type lectin receptor, CLEC12A, in facilitating dendritic cells binding and transmigration across the blood brain barrier in response to CCL2 chemotaxis. To test function of CLEC12A in an animal model of multiple sclerosis, they administered blocking antibody to CLEC12A that significantly ameliorated disease scores in MOG_35–55-induced progressive, as well as PLP_138–151-induced relapsing-remitting experimental autoimmune encephalomyelitis (EAE) mice. [Sci Rep] Full Article

Allergen-Encoding Bone Marrow Transfer Inactivates Allergic T Cell Responses, Alleviating Airway Inflammation

Researchers tested whether memory Th2 cell responses were silenced using a therapeutic approach where allergen expression in DCs is transferred to sensitized recipients using bone marrow (BM) cells as a vector for therapeutic gene transfer. Development of allergen-specific Th2 responses and allergen-induced airway inflammation was blocked by expression of allergen in DCs. Adoptive transfer studies showed that Th2 responses were inactivated by a combination of deletion and induction of T cell unresponsiveness. Transfer of BM encoding allergen expression targeted to DCs terminated, in an allergen-specific manner, Th2 responses in sensitized recipients. [JCI Insight] Full Article | Press Release

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Chemokines in the Cancer Microenvironment and their Relevance in Cancer Immunotherapy

Scientists focus on the main chemokines that are found in the human tumor microenvironment; they elaborate on their patterns of expression, their regulation and their roles in immune cell recruitment and in cancer and stromal cell biology, and they consider how they affect cancer immunity and tumorigenesis. They also discuss the potential of targeting chemokine networks, in combination with other immunotherapies, for the treatment of cancer. [Nat Rev Immunol] Abstract

The Emerging Role of Anti-CD25 Directed Therapies as Both Immune Modulators and Targeted Agents in Cancer

The authors discuss how the relative clinical safety and efficacy of administering anti-CD25 radioimmunoconjugates and immunotoxins in various hematological tumor indications has been established and clinical trials of a novel CD25-directed antibody drug conjugate are underway. [Br J Haematol] Abstract

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Abramson Cancer Center Studies Show Hope for Multiple Cancers with Pembrolizumab Combination Therapies

The combination of pembrolizumab and the checkpoint inhibitor known as epacadostat has lead to promising responses and has been generally well tolerated in patients with triple-negative breast cancer, non-small cell lung cancer, squamous cell cancer of the head and neck, and several other cancers. [Press release from Penn Medicine discussing research to be presented at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago] Press Release

Personalized Cell Therapy Combined with Ibrutinib Achieves Complete Remission in High Percentage of Chronic Lymphocytic Leukemia Patients

Combining the kinase inhibitor ibrutinib with an investigational personalized cellular therapy known as CTL119 can lead to complete remission in patients with high-risk chronic lymphocytic leukemia. The team will present the results from its pilot study of this combination therapy. [Press release from Penn Medicine discussing research to be presented at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago] Press Release

Triple Therapy for Rare Skin Cancer Shows Promise in Small, Early-Stage Trial

Three out of four patients treated with an experimental combination of three different therapies for the rare skin cancer known as Merkel cell carcinoma are in complete remission following the treatment, according to study results from a small clinical trial led at Fred Hutchinson Cancer Research Center. Fred Hutch immunotherapy researcher Dr. Kelly Paulson will present interim results from that study and a previous double-therapy study in a poster. [Press release from Fred Hutch discussing research to be presented at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago] Press Release

Array BioPharma and Bristol-Myers Squibb Announce Strategic Collaboration

Array BioPharma and Bristol-Myers Squibb announced the companies have entered into a clinical research collaboration to investigate the safety, tolerability and efficacy of Array’s investigational MEK inhibitor, binimetinib in combination with Bristol-Myers Squibb’s Opdivo and Opdivo + Yervoy regimen as a potential treatment for metastatic colorectal cancer in patients with microsatellite stable tumors. [Array BioPharma] Press Release

Bristol-Myers Squibb and Seattle Genetics Expand Clinical Collaboration to Evaluate Combination of Opdivo (Nivolumab) and ADCETRIS^® (Brentuximab Vedotin) in Pivotal Phase III Clinical Trial in Relapsed Hodgkin Lymphoma

Bristol-Myers Squibb Company and Seattle Genetics, Inc. announced that the companies have entered into a collaboration agreement to evaluate the combination of Bristol-Myers Squibb’s immunotherapy Opdivo and Seattle Genetics’ antibody-drug conjugate ADCETRIS in a pivotal Phase III clinical trial. [Bristol-Myers Squibb Company] Press Release

With Nearly Three Years of Follow-Up, KEYTRUDA^® (Pembrolizumab) Data Demonstrated Improved Survival Benefit Compared to Ipilimumab in Advanced Melanoma

Merck announced updated longer-term overall survival data from KEYNOTE-006, the Phase III study evaluating KEYTRUDA^®, the company’s anti-PD-1 therapy, in patients with unresectable or metastatic melanoma. The data showed sustained superior survival outcomes for patients receiving KEYTRUDA compared to ipilimumab in patients who were treatment-naïve or received one prior line of therapy for the treatment of advanced melanoma. [Merck] Press Release

Celyad Obtains Additional US Patent for Cancer Treatment Based on TCR-Deficient Allogeneic CAR-T Cells

Celyad announced the issuance of United States (US) Patent No. 9,663,763 relating to Celyad’s method of treating cancer by administering allogeneic primary human T cells that are engineered to be T-cell receptor (TCR)-deficient and to express a chimeric antigen receptor (CAR). [Celyad] Press Release

Progenitor Life Sciences, Developer of Technologies for ‘Off-the-Shelf’ Cellular Immunotherapies, Announces Its Proprietary Stealth™ Immune-Compatibility Platform

Progenitor announces Stealth™ platform enabling sourcing of cells from a wide range of healthy donors, without donor-recipient HLA-matching. Stealth™-engineered cells also reduce immune-mediated adverse events caused by unintended activation of the recipient’s immune system following infusion of engineered cell therapies. [Progenitor Life Sciences (Business Wire, Inc.)] Press Release

Intensity Therapeutics, Inc. Successfully Administers INT230-6 to First Patient in a Phase I/II Trial

Intensity Therapeutics, Inc. announced that the first patient successfully received treatment with the company’s lead product, INT230-6, as part of a Phase I/II international clinical study. [Intensity Therapeutics Inc.] Press Release

UK Election: Science Spending Pledges Overshadowed by Brexit

Ahead of a UK election that will decide who leads the country’s exit negotiations with the European Union, a remarkable consensus has emerged among the main national parties. All three have pledged in their manifestos to spend more money on science. Each is “putting science at the heart of their program for the future of Britain”, says Sarah Main, director of the London-based Campaign for Science and Engineering. Yet as the uncertainty of Brexit hangs over the future of British science, for many researchers the promises may seem more like consolation prizes. [Nature News] Editorial

Trials of Embryonic Stem Cells to Launch in China

In the next few months, surgeons in the Chinese city of Zhengzhou will carefully drill through the skulls of people with Parkinson’s disease and inject four million immature neurons derived from human embryonic stem cells into their brains. Then they will patch the patients up, send them home and wait. This will mark the start of the first clinical trial in China using human embryonic stem (ES) cells, and the first one worldwide aimed at treating Parkinson’s disease using ES cells from fertilized embryos. In a second trial starting around the same time, a different team in Zhengzhou will use ES cells to target vision loss caused by age-related macular degeneration. [Nature News] Editorial

Web of Science Owner Buys up Booming Peer-Review Platform

The owner of the vast science-citation database Web of Science — Clarivate Analytics — is buying up a firm that has gathered hundreds of thousands of peer-review records, in a deal that could lead to new ways of organizing scientific peer review and preventing peer-review fraud. [Nature News] Editorial

NEW 3^rd CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference
September 6-9, 2017
Mainz/Frankfurt, Germany

NEW Tumor Immunology and Immunotherapy
October 1-4, 2017
Boston, United States

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NEW Postdoctoral Position – Tumor Immunology and Cancer Immunotherapy (VIB-KU Leuven Center for Cancer Biology)

Scientific Sales Representative – Cell Separation (STEMCELL Technologies Inc.)

Postdoctoral Fellow – Neuroimmunology (The University of Texas MD Anderson Cancer Center)

Immunologist – Brain Cancer (Columbia University)

Postdoctoral Position – Cancer Immunology and Immunotherapy (Weill Cornell Medicine)

Scientist I – T Cell Immunology (Celgene Corporation)

Scientist – Analytical Development (KBI Biopharma)

Senior Scientist – Molecular and Cellular Neuroimmunology (Pfizer)

Postdoctoral Associate Position – Immunometabolism and Myeloid Cell Regulation within the Tumor Microenvironment (University of Louisville)

Principal Scientist – Immuno Oncology (Celgene Corporation)

Assistant Associate or Full Member – Cancer Immunology (Fred Hutchinson Cancer Research Center)

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