Weekly Top Scientific Research Review (20/3/2017 – 25/3/2017)

This week, we provide materials about temporal mixture modeling resolves TH1/TFH fate bifurcation, cancer epigenome, PARP inhibitors, mimicry of HIV neutralizing antibody and pediatric brain tumors treatment. Let’s learn together!

1. Single-cell RNA-seq and computational analysis using temporal mixture modeling resolves TH1/TFH fate bifurcation in malaria.

Differentiation of naïve CD4+ T cells into functionally distinct T helper (TH) subsets is crucial for the orchestration of immune responses. Because of extensive heterogeneity and multiple overlapping transcriptional programs in differentiating T cell populations, this process has remained a challenge for systematic dissection in vivo. By using single-cell transcriptomics and computational analysis with a temporal mixtures of Gaussian processes model, termed GPfates, Tapio Lönnberg at European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus in Hinxton, Cambridge, U.K and his colleagues reconstructed the developmental trajectories of TH1 and TFH (T follicular helper) cells during blood-stage Plasmodium infection in mice. By tracking clonality using endogenous T cell receptor sequences, the team first demonstrated that TH1/TFH bifurcation had occurred at both population and single-clone levels. Next, they identified genes whose expression was associated with TH1 or TFH fates and demonstrated a T cell-intrinsic role for Galectin-1 in supporting TH1 differentiation. They also revealed the close molecular relationship between TH1 and interleukin-10-producing Tr1 cells in this infection. TH1 and TFH fates emerged from a highly proliferative precursor that up-regulated aerobic glycolysis and accelerated cell cycling as cytokine expression began. Dynamic gene expression of chemokine receptors around bifurcation predicted roles for cell-cell interaction in driving TH1/TFH fates. In particular, they found that precursor TH cells were coached toward a TH1 but not a TFH fate by inflammatory monocytes. Thus, by integrating genomic and computational approaches, their study has provided two unique resources: a database, www.PlasmoTH.org, which facilitates discovery of novel factors controlling TH1/TFH fate commitment, and, more generally, GPfates, a modeling framework for characterizing cell differentiation toward multiple fates.

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2. The cancer epigenome: Concepts, challenges, and therapeutic opportunities.

Cancer biology is profoundly influenced by changes in the epigenome. Because the dynamic plasticity of the epigenome lends itself well to therapeutic manipulation, the past few years have witnessed an unprecedented investment in the development, characterization, and translation of targeted epigenetic therapies. In this review, Mark A. Dawson at Cancer Research Division, Peter MacCallum Cancer Centre in Melbourne, VIC, Australia  provide a broad context for recent developments that offer a greater understanding of how epigenetic regulators facilitate the initiation, maintenance, and evolution of cancer. He discuss newly developed epigenetic therapies and the cellular and molecular mechanisms that may govern sensitivity and resistance to these agents. He also review the rationale for future combination therapies involving existing and emerging epigenetic drugs.

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3. PARP inhibitors: Synthetic lethality in the clinic.

PARP inhibitors (PARPi), a cancer therapy targeting poly(ADP-ribose) polymerase, are the first clinically approved drugs designed to exploit synthetic lethality, a genetic concept proposed nearly a century ago. Tumors arising in patients who carry germline mutations in either BRCA1 or BRCA2 are sensitive to PARPi because they have a specific type of DNA repair defect. PARPi also show promising activity in more common cancers that share this repair defect. However, as with other targeted therapies, resistance to PARPi arises in advanced disease. In addition, determining the optimal use of PARPi within drug combination approaches has been challenging. Nevertheless, the preclinical discovery of PARPi synthetic lethality and the route to clinical approval provide interesting lessons for the development of other therapies. Here, Christopher J. Lord at The Cancer Research UK Gene Function Laboratory and Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research in London, UK and his colleagues discuss current knowledge of PARP inhibitors and potential ways to maximize their clinical effectiveness.

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4. Mimicry of an HIV broadly neutralizing antibody epitope with a synthetic glycopeptides.

Weekly Top Scientific Research Review (20/3/2017 – 25/3/2017)A goal for an HIV-1 vaccine is to overcome virus variability by inducing broadly neutralizing antibodies (bnAbs). One key target of bnAbs is the glycan-polypeptide at the base of the envelope (Env) third variable loop (V3). S. Munir Alam at Duke Human Vaccine Institute, Duke University School of Medicine in Durham, USA and his colleagues have designed and synthesized a homogeneous minimal immunogen with high-mannose glycans reflective of a native Env V3-glycan bnAb epitope (Man9-V3). V3-glycan bnAbs bound to Man9-V3 glycopeptide and native-like gp140 trimers with similar affinities. Fluorophore-labeled Man9-V3 glycopeptides bound to bnAb memory B cells and were able to be used to isolate a V3-glycan bnAb from an HIV-1-infected individual. In rhesus macaques, immunization with Man9-V3 induced V3-glycan-targeted antibodies. Thus, the Man9-V3 glycopeptide closely mimics an HIV-1 V3-glycan bnAb epitope and can be used to isolate V3-glycan bnAbs, the authors suggest.

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5. Disrupting the CD47-SIRPα anti-phagocytic axis by a humanized anti-CD47 antibody is an efficacious treatment for malignant pediatric brain tumors.

Morbidity and mortality associated with pediatric malignant primary brain tumors remain high in the absence of effective therapies. Macrophage-mediated phagocytosis of tumor cells via blockade of the anti-phagocytic CD47-SIRPα interaction using anti-CD47 antibodies has shown promise in preclinical xenografts of various human malignancies. Sharareh Gholamin at Lucile Packard Children’s Hospital, Stanford University School of Medicine in Stanford, CA, USA and her colleagues demonstrate the effect of a humanized anti-CD47 antibody, Hu5F9-G4, on five aggressive and etiologically distinct pediatric brain tumors: group 3 medulloblastoma (primary and metastatic), atypical teratoid rhabdoid tumor, primitive neuroectodermal tumor, pediatric glioblastoma, and diffuse intrinsic pontine glioma. Hu5F9-G4 demonstrated therapeutic efficacy in vitro and in vivo in patient-derived orthotopic xenograft models. Intraventricular administration of Hu5F9-G4 further enhanced its activity against disseminated medulloblastoma leptomeningeal disease. Notably, Hu5F9-G4 showed minimal activity against normal human neural cells in vitro and in vivo, a phenomenon reiterated in an immunocompetent allograft glioma model. Thus, Hu5F9-G4 is a potentially safe and effective therapeutic agent for managing multiple pediatric central nervous system malignancies, the authors suggest.

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