Immune Regulation News Volume 9.19 | May 26 2017

TOP STORY

Cancer Therapy May Work in Unexpected Way

Antibodies to the proteins PD-1 and PD-L1 have been shown to fight cancer by unleashing the body’s T cells, a type of immune cell. Researchers have shown that the therapy also fights cancer in a completely different way, by prompting immune cells called macrophages to engulf and devour cancer cells. [Press release from Stanford Medicine discussing online prepublication in Nature] Press Release | Abstract

(Ranked by impact factor of the journal)

Chromatin States Define Tumor-Specific T Cell Dysfunction and Reprogramming

Scientists showed that T cells in mouse tumors differentiate through two discrete chromatin states: a plastic dysfunctional state from which T cells can be rescued, and a fixed dysfunctional state in which the cells are resistant to reprogramming. They identified surface markers associated with each chromatin state that distinguished reprogrammable from non-reprogrammable PD1^hi dysfunctional T cells within heterogeneous T cell populations from tumors in mice; these surface markers were also expressed on human PD1^hi tumor-infiltrating CD8 T cells. [Nature] Abstract

Ephrin B1–Mediated Repulsion and Signaling Control Germinal Center T Cell Territoriality and Function

The authors found that ephrin-B1 (EFNB1), a class B ephrin, was highly expressed by germinal center (GC) B cells and demarcated the GC tissue domain boundary. Although EFNB1 was not required for initial GC formation or development of T_FH cells, its ablation from B cells led to exaggerated local accumulation of T_FH cells inside the GC. [Science] Abstract

Interferon-γ Drives T_reg Fragility to Promote Anti-Tumor Immunity

Using a mouse model of melanoma where neuropilin-1 (Nrp1)-deficient (Nrp1^–/–) and wild-type (Nrp1^+/+) regulatory T cells (T_regs) could be assessed in a competitive environment, investigators found that a high proportion of intratumoral Nrp1^–/– T_regs produce interferon-γ (IFNγ), which drives the fragility of surrounding wild-type T_regs, boosts anti-tumor immunity, and facilitates tumor clearance. They also showed that IFNγ-induced T_reg fragility was required for response to anti-PD1, suggesting that cancer therapies promoting T_reg fragility may be efficacious. [Cell] Abstract | Graphical Abstract

BACH2 Immunodeficiency Illustrates An Association between Super-Enhancers and Haploinsufficiency

Scientists describe a syndrome of BACH2-related immunodeficiency and autoimmunity that results from BACH2 haploinsufficiency. Affected subjects had lymphocyte-maturation defects that caused immunoglobulin deficiency and intestinal inflammation. The mutations disrupted protein stability by interfering with homodimerization or by causing aggregation. [Nat Immunol] Abstract

Antigen-Specific CD8⁺ T Cell Feedback Activates NLRP3 Inflammasome in Antigen-Presenting Cells through Perforin

Investigators showed that CD8⁺ T-cell feedback activates the NLRP3 inflammasome in antigen-presenting cells in an antigen-dependent manner to promote IL-1β maturation. [Nat Commun] Full Article

Macrophages Are Necessary for Epimorphic Regeneration in African Spiny Mice

Researchers used an emerging mammalian model of epimorphic regeneration, the African spiny mouse, to examine cell-based inflammation and tested the hypothesis that macrophages are necessary for regeneration. [eLife] Full Article | Press Release

An Immunogenic Phenotype in Paternal Antigen-Specific CD8⁺ T Cells at Embryo Implantation Elicits Later Fetal Loss in Mice

The role and regulation of specific phenotypes of CD8⁺ T cells in mediating pregnancy tolerance is not clear. Scientists aimed to investigate the impact on pregnancy outcome of altering the cytokine environment during maternal CD8⁺ T cell priming in early pregnancy. [Immunol Cell Biol] Abstract

The Metabolic Regulator mTORC1 Controls Terminal Myeloid Differentiation

Using a Ccr2/Cx₃cr1 dual-reporter system to model murine monocyte ontogeny, researchers conducted a small-molecule screen that identified an essential role of mechanistic target of rapamycin complex 1 (mTORC1) in the development of monocytes and other myeloid cells. Confirmatory studies using mice with inducible deletion of the mTORC1 component Raptor demonstrated absence of mature circulating monocytes, as well as disruption in neutrophil and dendritic cell development, reflecting arrest of terminal differentiation at the granulocyte-monocyte progenitor stage. [Sci Immunol] Full Article

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Therapeutic T Cell Engineering

Scientists discuss how engineered T cells are applicable in principle to many cancers, pending further progress to identify suitable target antigens, overcome immunosuppressive tumor microenvironments, reduce toxicities, and prevent antigen escape. Advances in the selection of optimal T cells, genetic engineering, and cell manufacturing are poised to broaden T-cell-based therapies and foster new applications in infectious diseases and autoimmunity. [Nature] Abstract

Microbiota in T-Cell Homeostasis and Inflammatory Diseases

The authors focus on understanding the complicated microbiota-T-cell axis between homeostatic and pathogenic conditions and elucidate important insights for the development of novel targets for disease therapy. [Exp Mol Med] Full Article

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Immunotherapy Data from CRI Clinical Accelerator to Be Presented

The Cancer Research Institute (CRI) announced that data from four of its Anna-Maria Kellen Clinical Accelerator early-phase immunotherapy combination trials will be presented. [Press release from the Cancer Research Institute discussing research to be presented at the American Society for Clinical Oncology (ASCO) Annual Meeting, Chicago] Press Release

AstraZeneca Delivers New Data on Expanding Portfolio of Cancer Medicines

AstraZeneca, along with its global biologics research and development arm, MedImmune, will demonstrate how it is rapidly delivering on the company’s science-led strategy for transformational cancer medicine development. [Press release from AstraZeneca discussing research to be presented at the American Society for Clinical Oncology Annual (ASCO) Meeting, Chicago] Press Release

PCI Biotech and Rxi Pharmaceuticals Extend Research Collaboration to the Field of Immuno-Oncology

PCI Biotech and RXi Pharmaceuticals announced that they are extending their preclinical research collaboration. [PCI Biotech] Press Release

U of T Research Helps Pave the Way for an Off-the-Shelf Supply of Cells for Immunotherapy

Two U of T students have developed new technologies that clear some of the barriers to having a limitless source of cells to target cancer and other diseases. These breakthroughs, described in two recent papers published in Nature Communications and Nature Methods and funded by Medicine by Design and the Ontario Institute for Regenerative Medicine, could lead to new cell therapies for boosting patients’ immune systems against disease, and for cancer immunotherapy, in which immune cells can be engineered to attack tumors. [University of Toronto] Press Release

$100 Million Gift Establishes Duchossois Family Institute to Develop ‘New Science’ Focused on Optimizing Health

A Chicago-area family with a deep commitment to supporting science and medicine gave $100 million to establish The Duchossois Family Institute at the University of Chicago Medicine, which seeks to accelerate research and interventions based on how the human immune system, microbiome and genetics interact to maintain health. [The University of Chicago Medicine] Press Release

FDA Approves First Cancer Treatment for Any Solid Tumor with a Specific Genetic Feature

The U.S. Food and Drug Administration (FDA) granted accelerated approval to a treatment for patients whose cancers have a specific genetic feature (biomarker). This is the first time the agency has approved a cancer treatment based on a common biomarker rather than the location in the body where the tumor originated. [The U.S. Food and Drug Administration] Press Release | Editorial

Sanofi and Regeneron Announce FDA Approval of Kevzara^® (Sarilumab) for the Treatment of Moderately to Severely Active Rheumatoid Arthritis in Adult Patients

Sanofi and Regeneron Pharmaceuticals, Inc. announced the U.S. Food and Drug Administration (FDA) approval of Kevzara^® for the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response or intolerance to one or more disease modifying antirheumatic drug. Kevzara is a human monoclonal antibody that binds to the interleukin-6 receptor (IL-6R), and has been shown to inhibit IL-6R mediated signaling. IL-6 is a cytokine in the body that, in excess and over time, can contribute to the inflammation associated with RA. [Sanofi] Press Release

X4 Pharmaceuticals Announces Initiation of the Phase II Expansion of Its Phase I/II Study of X4P-001 in Patients with Advanced Clear Cell Renal Cell Carcinoma

X4 Pharmaceuticals announced dosing of the first patient in the Phase II portion of the ongoing Phase I/II study evaluating X4P-001, the company’s lead CXCR4 inhibitor, in combination with Inlyta^® in patients with advanced clear cell renal cell carcinoma. Recent studies demonstrate that CXCR4/CXCL12 is a primary receptor-ligand pair that cancer cells and surrounding stromal cells use to block normal immune function and promote angiogenesis through the trafficking of T-effector and T-regulatory cells, as well as myeloid derived suppressor cells, in the tumor microenvironment. [X4 Pharmaceuticals] Press Release

How NSF Cut 11% from Its Budget

Donald Trump planned to include an 11% cut to National Science Foundation’s (NSF’s) $7.4 billion budget in his first full spending request to Congress. The news—which was publicly unveiled as part of the president’s $4.1 trillion budget for 2018—sent Jim Olds, who leads the biology directorate at the NSF, and the heads of NSF’s other six research and education programs scrambling to erase big chunks of their portfolios without sacrificing NSF’s ability to fund the best new ideas. [ScienceInsider] Editorial

Academies Calculate How Much Brexit Will Cost U.K. Researchers

Some academic fields in the United Kingdom will have major funding holes to fill once the country leaves the European Union, according to new research commissioned by four U.K. academies. [ScienceInsider] Editorial

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