Human Immunology News Volume 5.18 | May 9 2017

TOP STORY

Immune Cells Derived from Specialized Progenitors

Dendritic cells are gatekeepers of immunity and are crucial for the detection and initiation of immunity against pathogens and foreign substances. Up to now dendritic cell subtypes were thought to develop from one common progenitor. Researchers have shown with single cell resolution that this important component of the human immune system develops from specialized progenitors. [Press release from the University of Bonn discussing online prepublication in Science] Press Release | Abstract

(Ranked by impact factor of the journal)

Innate Immune Landscape in Early Lung Adenocarcinoma by Paired Single-Cell Analyses

To guide the design of immunotherapy strategies for patients with early stage lung tumors, investigators developed a multiscale immune profiling strategy to map the immune landscape of early lung adenocarcinoma lesions to search for tumor-driven immune changes. Utilizing a barcoding method that allows a simultaneous single-cell analysis of the tumor, non-involved lung, and blood cells, they provide a detailed immune cell atlas of early lung tumors. [Cell] Full Article | Press Release | Graphical Abstract

An Immune Atlas of Clear Cell Renal Cell Carcinoma

Scientists used mass cytometry with extensive antibody panels to perform in-depth immune profiling of samples from 73 clear cell renal cell carcinoma patients and five healthy controls. In 3.5 million measured cells, they identified 17 tumor-associated macrophage phenotypes, 22 T cell phenotypes, and a distinct immune composition correlated with progression-free survival, thereby presenting an in-depth human atlas of the immune tumor microenvironment in this disease. [Cell] Full Article | Press Release | Graphical Abstract

Tumor-Residing Batf3 Dendritic Cells Are Required for Effector T Cell Trafficking and Adoptive T Cell Therapy

By using a tumor model resembling non-T cell-inflamed human tumors, the authors assessed whether adoptive T cell transfer might overcome failed spontaneous priming. Flow cytometric assays combined with intra-vital imaging indicated failed trafficking of effector T cells into tumors. Mechanistically, this was due to the absence of CXCL9/10, which they found to be produced by CD103⁺ dendritic cells in T cell-inflamed tumors. [Cancer Cell] Abstract | Graphical Abstract

CHD4 Has Oncogenic Functions in Initiating and Maintaining Epigenetic Suppression of Multiple Tumor Suppressor Genes

An oncogenic role for CHD4, a NuRD component, has been defined for initiating and supporting tumor suppressor gene silencing in human colorectal cancer. CHD4 recruits repressive chromatin proteins to sites of DNA damage repair, including DNA methyltransferases where it imposes de novo DNA methylation. At tumor suppressor genes, CHD4 retention helped maintain DNA hypermethylation-associated transcriptional silencing. CHD4 was recruited by the excision repair protein OGG1 for oxidative damage to interact with the damage-induced base 8-hydroxydeoxyguanosine, while ZMYND8 recruited it to double-strand breaks. [Cancer Cell] Abstract | Graphical Abstract

Single-Cell RNA-Seq Enables Comprehensive Tumor and Immune Cell Profiling in Primary Breast Cancer

At a single-cell resolution, carcinoma cells displayed common signatures within the tumor as well as intratumoral heterogeneity regarding breast cancer subtype and crucial cancer-related pathways. Most of the non-cancer cells were immune cells, with three distinct clusters of T lymphocytes, B lymphocytes and macrophages. T lymphocytes and macrophages both displayed immunosuppressive characteristics: T cells with a regulatory or an exhausted phenotype and macrophages with an M2 phenotype. [Nat Commun] Full Article

A Rational Strategy for Reducing On-Target Off-Tumor Effects of CD38-Chimeric Antigen Receptors by Affinity Optimization

Investigators identified CD38-chimeric antigen receptor (CAR) T cells of ~1000- fold reduced affinity which optimally proliferated, produced Th1 like cytokines and effectively lysed CD38⁺⁺ multiple myeloma cells but spared CD38⁺ healthy hematopoietic cells, in vitro and in vivo. Their systematic approach is highly suitable for the generation of optimal CARs for effective and selective targeting of tumor-associated antigens. [Mol Ther] Abstract

T-Cell Infiltration and Clonality Correlate with Programmed Cell Death Protein 1 and Programmed Death-Ligand 1 Expression in Patients with Soft Tissue Sarcomas

The authors identified patients with the common soft tissue sarcoma soft tissue sarcoma subtypes: leiomyosarcoma, undifferentiated pleomorphic sarcoma, synovial sarcoma, well-differentiated/dedifferentiated liposarcoma, and myxoid/round cell liposarcoma. Gene expression, immunohistochemistry for programmed cell death protein and programmed death-ligand 1, and T-cell receptor Vβ gene sequencing were performed on formalin-fixed, paraffin-embedded tumors from 81 patients. Differences in liposarcoma subsets were also evaluated. [Cancer] Full Article | Press Release

Transcriptional Regulation of FOXP3 Requires Integrated Activation of Both Promoter and CNS Regions in Tumor-Induced CD8⁺ Treg Cells

Researchers report an augmentation CD8⁺FOXP3⁺ Tregs in breast tumor microenvironment. FOXP3, the lineage-specific transcription factor, is a dominant regulator of Treg cell development and function. FOXP3 is induced preferentially by divergent signaling in CD4⁺ Treg cells. But how FOXP3 is induced and maintained in tumor-CD8⁺ Tregs is the Cinderella of the investigation. They observed that RUNX3, a CD8⁺ lineage-specific transcription factor, binds at the FOXP3-promoter to induce its transcription. [Sci Rep] Full Article

Platelets Subvert T Cell Immunity against Cancer via GARP-TGFβ Axis

Scientists hypothesized that platelets promote malignancy and resistance to therapy by dampening host immunity. They showed that genetic targeting of platelets enhances adoptive T cell therapy of cancer. An unbiased biochemical and structural biology approach established transforming growth factor β (TGFβ) and lactate as major platelet-derived soluble factors to obliterate CD4⁺ and CD8⁺ T cell functions. [Sci Immunol] Abstract | Press Release

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Antigen-Inexperienced Memory CD8⁺ T Cells: Where They Come from and Why We Need Them

Memory-phenotype CD8⁺ T cells exist in substantial numbers within hosts that have not been exposed to either foreign antigen or overt lymphopenia. These antigen-inexperienced memory-phenotype T cells can be divided into two major subsets: ‘innate memory’ T cells and ‘virtual memory’ T cells. Scientists review the available literature on each subset, highlighting the key differences between these populations. They suggest a unifying model for the categorization of antigen-inexperienced memory-phenotype CD8⁺ T cells. [Nat Rev Immunol] Abstract

Is Autoimmunity the Achilles’ Heel of Cancer Immunotherapy?

The authors discuss evidence that the occurrence of immunotoxicity bodes well for the patient, and describe mechanisms that might be related to the induction of autoimmunity. They explore approaches to limit immunotoxicity, and discuss the future directions of research and reporting that are needed to diminish it. [Nat Med] Abstract

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Syros Announces Late-Breaking Oral Presentation on Its Research Identifying Key Genes that Control the Auto-Immune Response in Lupus

Syros Pharmaceuticals announced that the company’s research identifying key genes that control T cell activation in systemic lupus erythematosus will be highlighted in a late-breaking oral presentation. [Press release from Syros Pharmaceuticals discussing research to be presented at the 17^th Annual Meeting of the Federation of Clinical Immunology Societies (FOCIS), Chicago] Press Release

Be The Match BioTherapies Announces Collaboration Agreement with Magenta Therapeutics

Be The Match BioTherapies^SM announced that it has entered into a strategic partnership with Magenta Therapeutics. The collaboration is intended to support efforts to improve transplant outcomes and expand the application of stem cell transplantation into disease indications that include autoimmunity, serious inherited immune and metabolic disorders, blood defects and blood cancers. [Be The Match BioTherapies^SM] Press Release

Celyad Grants to Novartis a Non-Exclusive License for Its Allogeneic TCR-Deficient CAR-T Cells Patents

Celyad announced a non-exclusive license agreement with Novartis for Celyad’s US patents for the production of allogeneic chimeric antigen receptor (CAR)-T cells. [Celyad] Press Release

Concert Pharmaceuticals Initiates CTP-543 Phase II Trial in Alopecia Areata

Concert Pharmaceuticals, Inc. announced the initiation of a Phase IIa clinical trial evaluating CTP-543 for the treatment of moderate-to-severe alopecia areata, an autoimmune disorder in which the immune system attacks hair follicles, resulting in patchy or complete hair loss. CTP-543 is an orally-administered selective inhibitor of Janus kinases 1 and 2 which are enzymes believed to be involved in this autoimmune disorder. [Concert Pharmaceuticals, Inc.] Press Release

NantKwest and NantCell Announce FDA Authorization for the NANT Cancer Vaccine Clinical Trials, the First Novel Combination of Innate and Adaptive Immunotherapy in Patients with Pancreatic Cancer

NantCell and NantKwest Inc. announced that the U.S. Food & Drug Administration (FDA) has authorized an Investigational New Drug Application for the NANT Cancer Vaccine for clinical trial enrollment for pancreatic cancer patients. [NantKwest Inc.] Press Release

Biotech Execs, Academic Leaders Make Case for NIH Funding at White House Meeting

Could the Trump administration be changing its mind about slashing funding for the National Institutes of Health (NIH)? Scientific leaders were optimistic after meeting at the White House with several biotech executives to discuss the “ecosystem” in which federally funded basic research leads to discoveries that companies turn into treatments. [ScienceInsider] Editorial

Scientists Relieved by Emmanuel Macron’s French Election Victory

French scientists say they’re relieved and happy that their country’s next president will be Emmanuel Macron, a 39-year-old former civil servant and economy minister who swept to victory in elections. Macron intends to make cuts to public spending, but has said he will ring-fence the budgets for research and higher education, areas that he wants to make the central plank of a program to boost innovation and cut unemployment. [Nature News] Editorial

Money Still Missing as the Plan to Synthesize a Human Genome Takes Another Step Forward

More than 200 biologists, business people, and ethicists will converge upon the New York Genome Center in Manhattan to jumpstart what they hope will be biology’s next blockbuster: Genome Project-write, a still-unfunded sequel to the Human Genome Project where instead of reading a human genome, scientists create one from scratch and incorporate it into cells for various research and medical purposes. [ScienceInsider] Editorial

NEW The TGF-β Superfamily: Signaling in Development and Disease
July 9-14, 2017
Lisbon, Portugal

NEW Autoimmunity
July 9-14, 2017
Saxtons River, Vermont, United States

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NEW Scientist – Analytical Development (KBI Biopharma)

NEW Postdoctoral Research Associate – Molecular Microbiology and Immunology (University of Southern California)

NEW Senior Scientific Researcher – Personalized Cancer Vaccines (Genentech)

Tenure-Track Faculty Position(s) – Immunology (Cornell University)

Faculty Position – Cancer Immunology (Mayo Clinic)

Postdoctoral Fellow – Innate Immunity and Neurodegeneration (Mount Sinai Health System)

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

Postdoctoral Scholar – Multiple Sclerosis (University of Washington)

Postdoctoral Research Fellow – Inflammation and Immuno-Oncology (Yale School of Medicine)

Assistant Associate – Cancer Immunology (Fred Hutchinson Cancer Research Center)

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