Immune Regulation News Volume 9.21 | Jun 9 2017

TOP STORY

Stability and Function of Regulatory T Cells Expressing the Transcription Factor T-Bet

The authors demonstrated that expression of the T helper 1 (T_H1)-associated transcription factor T-bet in mouse regulatory T (T_reg) cells, induced at steady state and following infection, gradually becomes highly stable even under non-permissive conditions. Loss of function or elimination of T-bet-expressing Treg cells—but not of T-bet expression in Treg cells—resulted in severe T_H1 autoimmunity. [Nature] Abstract

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Cytochrome c Oxidase Activity Is a Metabolic Checkpoint that Regulates Cell Fate Decisions during T Cell Activation and Differentiation

Researchers explored the consequences of oxidative phosphorylation dysfunction in T cells. Since cytochrome c oxidase (COX) is a critical regulator of OXPHOS, they created a mouse model with isolated dysfunction in T cells by targeting a gene, COX10, that produces mitochondrial disease in humans. COX dysfunction resulted in increased apoptosis following activation in vitro and immunodeficiency in vivo. [Cell Metab] Abstract | Graphical Abstract

Dual Targeting Nanoparticle Stimulates the Immune System to Inhibit Tumor Growth

Scientists describe the development of a nanoparticle platform that overcomes the immunosuppressive tumor microenvironment. These nanoparticles were coated with two different antibodies that simultaneously block the inhibitory checkpoint PD-L1 signal and stimulated T cells via the 4-1BB co-stimulatory pathway. These “immunoswitch” particles significantly delayed tumor growth and extended survival in multiple in vivo models of murine melanoma and colon cancer in comparison to the use of soluble antibodies or nanoparticles separately conjugated with the inhibitory and stimulating antibodies. [ACS Nano] Abstract | Press Release | Graphical Abstract

Tregs Restrain Dendritic Cell Autophagy to Ameliorate Autoimmunity

Investigators have demonstrated that Foxp3⁺ Tregs potently suppress autoimmune responses in vivo through inhibition of the autophagic machinery in dendritic cells (DCs) in a cytotoxic T-lymphocyte–associated protein 4–dependent manner. Autophagy-deficient DCs exhibited reduced immunogenic potential and failed to prime autoantigen-specific CD4⁺ T cells to mediate autoimmunity. [J Clin Invest] Full Article

Ndfip1 Restricts mTORC1 Signaling and Glycolysis in Regulatory T Cells to Prevent Autoinflammatory Disease

Scientists showed that Ndfip1, a coactivator of Nedd4-family E3 ubiquitin ligases, is required for Foxp3⁺ T regulatory (T_reg) cell stability and function. Ndfip1 deletion in T_reg cells results in autoinflammatory disease. Ndfip1-deficient T_reg cells are highly proliferative and are more likely to lose Foxp3 expression to become IL-4-producing T_H2 effector cells. [Nat Commun] Full Article

The Ubiquitin Ligase ZNRF1 Promotes Caveolin-1 Ubiquitination and Degradation to Modulate Inflammation

Researchers revealed that E3 ubiquitin ligase ZNRF1 modulates caveolin-1 (CAV1) protein stability to regulate Toll-like receptor (TLR) 4-triggered immune responses. They demonstrated that ZNRF1 physically interacts with CAV1 in response to lipopolysaccharide and mediates ubiquitination and degradation of CAV1. The ZNRF1–CAV1 axis regulates Akt–GSK3β activity upon TLR4 activation, resulting in enhanced production of pro-inflammatory cytokines and inhibition of anti-inflammatory cytokine IL-10. [Nat Commun] Full Article

Innate and Adaptive Immunity Are Progressively Activated in Parallel with Renal Injury in the 5/6 Renal Ablation Model

Investigators performed a detailed analysis of the time course of innate and adaptive immunity activation in the 5/6 renal ablation (Nx) model. Munich-Wistar rats undergoing Nx were studied 15, 60 and 120 days after ablation. Hypertension, albuminuria, creatinine retention, interstitial expansion and infiltration by macrophages and T-lymphocytes were already evident 15 days after Nx. [Sci Rep] Full Article

Genetic and Small Molecule Disruption of the AID/RAD51 Axis Similarly Protects Nonobese Diabetic Mice from Type 1 Diabetes through Expansion of Regulatory B Lymphocytes

The authors found that CRISPR/Cas9-mediated ablation of the activation-induced cytidine deaminase gene required for class switch recombination/somatic hypermutation induction inhibits type 1 diabetes T1D development in the NOD mouse model. The activation-induced cytidine deaminase protein induced genome-wide DNA breaks that, if not repaired through RAD51-mediated homologous recombination, resulted in B lymphocyte death. [J Immunol] Abstract | Press Release

A Nonadjuvanted IgG2a Monoclonal Antibody against Nucleosomes Elicits Potent T Cell–Dependent, Idiotype-Specific IgG1 Responses and Glomerular IgG1/IgG2a Deposits in Normal Mice

Idiotypes (Ids) are unique epitopes of Ab V regions and can trigger anti-Id immune responses, but immunization with several nonadjuvanted isologous IgG mAbs has induced tolerance to their Ids. Scientists immunized non–lupus-prone mice with 11 allotype “a” of IgG2a (IgG2a^a) and 4 IgG2c nonadjuvanted, isologous mAbs purified from serum-free medium. Of five IgG2a^a mAbs with specificity for nucleosomes, the repeating histone-DNA subunit of chromatin, four elicited an IgG1 anti-mAb response and one mAb was nonimmunogenic. In contrast, none of six IgG2a^a mAbs with unknown specificity triggered anti-mAb responses. [J Immunol] Abstract

HCV T Cell Receptor Chain Modifications to Enhance Expression, Pairing, and Antigen Recognition in T Cells for Adoptive Transfer

One approach to promote proper T cell receptor (TCR) chain pairing involves modifications of the introduced TCR genes: introducing a disulfide bridge, substituting murine for human constant regions, codon optimization, TCR chain leucine zipper fusions, and a single-chain TCR. Researchers have introduced these modifications into a hepatitis C virus (HCV) reactive TCR and utilized a marker gene, CD34t, which allowed them to directly compare transduction efficiency with TCR expression and T cell function. Their results revealed that of the TCRs tested, T cells expressing the murine Cβ2 TCR or leucine zipper TCR had the highest levels of expression and the highest percentage of lytic and interferon-γ-producing T cells. [Mol Ther Oncolytics] Full Article

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Transcriptional Determination and Functional Specificity of Myeloid Cells: Making Sense of Diversity

The authors discuss the molecular basis of the differentiation of myeloid cells, which is controlled by transcription factors, transcriptional co-regulators and post-transcriptional mechanisms, and examine how the functional specification of the resulting mature immune cells of the myeloid lineage affects their response to danger signals. [Nat Rev Immunol] Abstract

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CAR T-Cell Therapy Sends Multiple Myeloma into Lasting Remission

In an early clinical trial, 33 out of 35 (94%) patients had clinical remission of multiple myeloma upon receiving a new type of immunotherapy – chimeric antigen receptor (CAR) T cells targeting B-cell maturation protein. Most patients had only mild side effects. [Press release from the American Society of Clinical Oncology (ASCO) discussing research presented at the 2017 American Society of Clinical Oncology, Chicago] Press Release

Using a Virus to Teach the Immune System to Kill Cancer

Researchers reported the results of an early-stage clinical trial of a cancer vaccine that uses an engineered virus to teach patients’ immune systems to recognize and kill tumor cells. [Press release from Fred Hutchinson Cancer Research Center discussing research presented at the 2017 American Society of Clinical Oncology (ASCO), Chicago] Press Release | Abstract

Two Combination Therapies Shrink Melanoma Brain Metastases in More than Half of Patients

A combination regimen of two immunotherapies and another of two targeted therapies each significantly shrank metastatic brain tumors in at least 50% of patients in separate multi-center clinical trials. [Press release from the University of Texas MD Anderson Cancer Center discussing research presented at the 2017 American Society of Clinical Oncology (ASCO), Chicago] Press Release

Immunotherapy Combination Shows Promise in Early Stage Triple Negative Breast Cancer

A Yale Cancer Center clinical trial combining the immune checkpoint inhibitor with chemotherapy as preoperative treatment for early stage triple negative breast cancer disclosed a 71% pathologic complete response to the combination treatment in the initial Phase I trial. By comparison, chemotherapies alone produce a pathologic complete response rate of only around 35-40% for women with triple negative breast cancer. [Press release from the University of Yale Cancer Center discussing research presented at the 2017 American Society of Clinical Oncology (ASCO), Chicago] Press Release

NantKwest Expands NANT Cancer Vaccine Program with Additional Clinical Trials Announced Addressing Multiple Cancer Types across All Stages of Disease

NantKwest and Nantworks announced the expansion of the company’s existing NANT Cancer Vaccine program in pancreatic cancer to target a number of additional tumor types. [Press release from NantKwest (2017 Business Wire, Inc.) discussing research presented at the 2017 American Society of Clinical Oncology (ASCO), Chicago] Press Release

ACEA Biosciences Announces Collaboration with Memorial Sloan Kettering Cancer Center on Personalized CAR T Cell Therapy

ACEA Biosciences and Memorial Sloan Kettering Cancer Center have entered into a collaboration to evaluate a personalized ex vivo potency assay using cancer patients’ malignant pleural effusions and ACEA’s xCELLigence Real-Time Cell Analysis instrument to monitor destruction of the cancer cells by the patient’s own genetically modified CAR T cells. [ACEA Biosciences] Press Release

Bristol-Myers Squibb Announces New Collaboration to Evaluate Combination Therapy in Colorectal Cancer

Bristol-Myers Squibb Company announced it has entered into a clinical research collaboration with Novartis to investigate the safety, tolerability and efficacy of Opdivo and Opdivo + Yervoy regimen in combination with Mekinist^®, as a potential treatment option for metastatic colorectal cancer in patients with microsatellite stable tumors where the tumors are proficient in mismatch repair. [Bristol-Myers Squibb Company] Press Release

Bristol-Myers Squibb and QIAGEN Sign Agreement for Use of NGS Technology to Develop Gene Expression Profiles for Immuno-Oncology Therapies

Bristol-Myers Squibb Company and QIAGEN have signed an agreement to explore the use of next-generation sequencing (NGS) technology to develop gene expression profiles as predictive or prognostic tools for use with Bristol-Myers Squibb novel immuno-oncology therapies in cancer treatment. [Bristol-Myers Squibb Company] Press Release

Warren Alpert Foundation Honors Five Pioneers in Cancer Immunology

The 2017 Warren Alpert Foundation Prize has been awarded to five scientists for transformative discoveries in the field of cancer immunology. Collectively, their work has elucidated foundational mechanisms in cancer’s ability to evade immune recognition and, in doing so, has profoundly altered the understanding of disease development and treatment. Their discoveries have led to the development of effective immune therapies for several types of cancer. [The President and Fellows of Harvard College] Press Release

UK Scientists Hope for Softened Brexit after Shock Election Result

The United Kingdom (UK)’s general election produced no clear outcome — but scientists trying to divine meaning from the chaos say they hope the result will ultimately benefit their country’s research ties with the European Union. [Nature News] Editorial

New Clues to Why a French Drug Trial Went Horribly Wrong

Scientists are one step closer to understanding how a clinical trial in France killed one volunteer and led to the hospitalization of five others. A new study shows that the compound tested in the study, BIA 10-2474, has effects on many other enzymes in addition to the one it was supposed to inhibit. These “off-target” effects might explain why the drug caused side effects ranging from headaches to irreversible brain damage. [ScienceInsider] Editorial

NEW Cell Symposium: Emerging and Re-Emerging Viruses
October 1-3, 2017
Arlington, Virginia, United States

NEW Society for Leucocyte Biology (SLB)
October 5-7, 2017
Vancouver, British Columbia, Canada

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NEW Scientist – Neuroinflammation (University Health Network (Toronto))

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

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

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)

Principal Scientist – Immuno Oncology (Celgene Corporation)

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

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