Phenotypic screening reveals TNFR2 as a promising target for cancer immunotherapy.

Antibodies that target cell-surface molecules on T cells can enhance anti-tumor immune responses, resulting in sustained immune-mediated control of cancer. We set out to find new cancer immunotherapy targets by phenotypic screening on human regulatory T (Treg) cells and report the discovery of novel activators of tumor necrosis factor receptor 2 (TNFR2) and a potential role for this target in immunotherapy. A diverse phage display library was screened to find antibody mimetics with preferential binding to Treg cells, the most Treg-selective of which were all, without exception, found to bind specifically to TNFR2. A subset of these TNFR2 binders were found to agonise the receptor, inducing iκ-B degradation and NF-κB pathway signalling in vitro. TNFR2 was found to be expressed by tumor-infiltrating Treg cells, and to a lesser extent Teff cells, from three lung cancer patients, and a similar pattern was also observed in mice implanted with CT26 syngeneic tumors. In such animals, TNFR2-specific agonists inhibited tumor growth, enhanced tumor infiltration by CD8+ T cells and increased CD8+ T cell IFN-γ synthesis. Together, these data indicate a novel mechanism for TNF-α-independent TNFR2 agonism in cancer immunotherapy, and demonstrate the utility of target-agnostic screening in highlighting important targets during drug discovery.GW, BM, SG, JC-U, AS, AG-M, CB, JJ, RL, AJL, SR, RS, LJ, VV-A, RM and RWW were funded by MedImmune; JP and VB were funded by AstraZeneca PLC; JW, RSA-L and JB were funded by NIHR Cambridge Biomedical Research Centre and Kidney Research UK; JS and JF were funded by Retrogenix Ltd

One Knob To Rule Them All: Reductionist Interfaces for Expansionist Research

This paper describes an instance of what we call `curated research', a concerted thinking, making and performance activity between two research teams with a dedicated interest in the creation of experimental musical instruments and the development of new performance practices. Our work builds theoretically upon critical work in philosophy, anthropology and aesthetics, and practically upon previous explorations of strategies for facilitating rapid, collaborative, publicly-oriented making in artistic settings. We explored an orientation to making which promoted the creation of a family of instruments and performance environments that were responses to the self-consciously provocative theme of `One Knob To Rule Them All'. A variety of design issues were explored including: mapping, physicality, the question of control in interface design, reductionist aesthetics and design strategies, and questions of gender and power in musical culture. We discuss not only the technologies which were made but also reflect on the value of such concerted, provocatively thematised, collective making activities for addressing foundational design issues. As such, our work is intended not just as a technical and practical contribution to NIME but also a reflective provocation into how we conduct research itself in a curated critical manner

Severe malaria is associated with parasite binding to endothelial protein C receptor

Sequestration of Plasmodium falciparum-infected erythrocytes in host blood vessels is a key triggering event in the pathogenesis of severe childhood malaria, which is responsible for about one million deaths every year(1). Sequestration is mediated by specific interactions between members of the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family and receptors on the endothelial lining(2). Severe malaria is associated with expression of specific PfEMP1 subtypes containing domain cassettes (DC) 8 and 13(3), but the endothelial receptor for parasites expressing these proteins was unknown(4,5). Here, we identify endothelial protein C receptor (EPCR), which mediates cytoprotective effects of activated protein C(6), as the endothelial receptor for DC8 and DC13 PfEMP1. We show that EPCR binding is mediated through the N-terminal cysteine-rich interdomain region (CIDRα1) of DC8 and group A PfEMP1 subfamilies and that CIDRα1 interferes with protein C binding to EPCR. This PfEMP1 adhesive property links P. falciparum cytoadhesion to a host receptor involved in anticoagulation and endothelial cytoprotective pathways and has implications for understanding malaria pathology and the development of new malaria interventions

Targeting Human Cancer by a Glycosaminoglycan Binding Malaria Protein

SummaryPlasmodium falciparum engineer infected erythrocytes to present the malarial protein, VAR2CSA, which binds a distinct type chondroitin sulfate (CS) exclusively expressed in the placenta. Here, we show that the same CS modification is present on a high proportion of malignant cells and that it can be specifically targeted by recombinant VAR2CSA (rVAR2). In tumors, placental-like CS chains are linked to a limited repertoire of cancer-associated proteoglycans including CD44 and CSPG4. The rVAR2 protein localizes to tumors in vivo and rVAR2 fused to diphtheria toxin or conjugated to hemiasterlin compounds strongly inhibits in vivo tumor cell growth and metastasis. Our data demonstrate how an evolutionarily refined parasite-derived protein can be exploited to target a common, but complex, malignancy-associated glycosaminoglycan modification