Tumour cells evade immune surveillance by upregulating the surface expression of programmed death-ligand 1 (PD-L1), which interacts with programmed death-1 (PD-1) receptor on T cells to elicit the immune checkpoint response. Anti-PD-1 antibodies have shown remarkable promise in treating tumours, including metastatic melanoma. However, the patient response rate is low. A better understanding of PD-L1-mediated immune evasion is needed to predict patient response and improve treatment efficacy. Here we report that metastatic melanomas release extracellular vesicles, mostly in the form of exosomes, that carry PD-L1 on their surface. Stimulation with interferon-γ (IFN-γ) increases the amount of PD-L1 on these vesicles, which suppresses the function of CD8 T cells and facilitates tumour growth. In patients with metastatic melanoma, the level of circulating exosomal PD-L1 positively correlates with that of IFN-γ, and varies during the course of anti-PD-1 therapy. The magnitudes of the increase in circulating exosomal PD-L1 during early stages of treatment, as an indicator of the adaptive response of the tumour cells to T cell reinvigoration, stratifies clinical responders from non-responders. Our study unveils a mechanism by which tumour cells systemically suppress the immune system, and provides a rationale for the application of exosomal PD-L1 as a predictor for anti-PD-1 therapy.

We review the current state of knowledge of phase separation and phase equilibria in porous materials. Our emphasis is on fundamental studies of simple fluids (composed of small, neutral molecules) and well-characterized materials. While theoretical and molecular simulation studies are stressed, we also survey experimental investigations that are fundamental in nature. Following a brief survey of the most useful theoretical and simulation methods, we describe the nature of gas-liquid (capillary condensation), layering, liquid-liquid and freezing/melting transitions. In each case studies for simple pore geometries, and also more complex ones where available, are discussed. While a reasonably good understanding is available for phase equilibria of pure adsorbates in simple pore geometries, there is a need to extend the models to more complex pore geometries that include effects of chemical and geometrical heterogeneity and connectivity. In addition, with the exception of liquid-liquid equilibria, little work has been done so far on phase separation for mixtures in porous media.

We present a review of experimental, theoretical, and molecular simulation studies of confinement effects on freezing and melting. We consider both simple and more complex adsorbates that are confined in various environments (slit or cylindrical pores and also disordered porous materials). The most commonly used molecular simulation, theoretical and experimental methods are first presented. We also provide a brief description of the most widely used porous materials. The current state of knowledge on the effects of confinement on structure and freezing temperature, and the appearance of new surface-driven and confinement-driven phases are then discussed. We also address how confinement affects the glass transition.

Summary Genetic studies have established anaplastic lymphoma kinase (ALK), a cell surface receptor tyrosine kinase, as a tractable molecular target in neuroblastoma. We describe comprehensive genomic, biochemical, and computational analyses of ALK mutations across 1596 diagnostic neuroblastoma samples. ALK tyrosine kinase domain mutations occurred in 8% of samples; at three hotspots plus 13 minor sites – and correlated significantly with poorer survival in high- and intermediate-risk neuroblastoma. Biochemical and computational studies distinguished oncogenic (constitutively activating) from non-oncogenic mutations and allowed robust computational prediction of their effects. We also established differential in vitro crizotinib sensitivity of mutated variants. Our studies identify ALK genomic status as a clinically important therapeutic stratification tool in neuroblastoma, and will allow tailoring of ALK-targeted therapy to specific mutations.

ErbB3/HER3 is one of four members of the human epidermal growth factor receptor (EGFR/HER) or ErbB receptor tyrosine kinase family. ErbB3 binds neuregulins via its extracellular region and signals primarily by heterodimerizing with ErbB2/HER2/Neu. A recently appreciated role for ErbB3 in resistance of tumor cells to EGFR/ErbB2-targeted therapeutics has made it a focus of attention. However, efforts to inactivate ErbB3 therapeutically in parallel with other ErbB receptors are challenging because its intracellular kinase domain is thought to be an inactive pseudokinase that lacks several key conserved (and catalytically important) residuesincluding the catalytic base aspartate. We report here that, despite these sequence alterations, ErbB3 retains sufficient kinase activity to robustly trans-autophosphorylate its intracellular regionalthough it is substantially less active than EGFR and does not phosphorylate exogenous peptides. The ErbB3 kinase domain binds ATP with a K d of approximately 1.1 μM. We describe a crystal structure of ErbB3 kinase bound to an ATP analogue, which resembles the inactive EGFR and ErbB4 kinase domains (but with a shortened αC-helix). Whereas mutations that destabilize this configuration activate EGFR and ErbB4 (and promote EGFR-dependent lung cancers), a similar mutation conversely inactivates ErbB3. Using quantum mechanics/molecular mechanics simulations, we delineate a reaction pathway for ErbB3-catalyzed phosphoryl transfer that does not require the conserved catalytic base and can be catalyzed by the "inactive-like" configuration observed crystallographically. These findings suggest that ErbB3 kinase activity within receptor dimers may be crucial for signaling and could represent an important therapeutic target.dimerization | kinase inhibitor | catalytic mechanism | activation loop R eceptor tyrosine kinases (RTKs) from the EGF receptor (EGFR) or ErbB/HER family play important roles in animal development and disease (1) and are the targets of several important therapeutic agents used clinically to treat cancer. Each receptor contains a large extracellular ligand-binding region (targeted by therapeutic antibodies), a single transmembrane helix, and an intracellular tyrosine kinase domain (TKD) that is flanked by juxtamembrane and C-terminal regulatory regions and is targeted by specific small-molecule kinase inhibitors (1, 2). Ligand binding to the extracellular region promotes homo-or heterodimerization of ErbB receptors, leading to allosteric activation of their intracellular kinase domains through the formation of asymmetric dimers (3-5). Within an activated dimer, the C-terminal regulatory tail is trans-autophosphorylated on tyrosines and recruits downstream signaling molecules that contain phosphotyrosine-binding Src homology-2 (SH2) domains.ErbB3/HER3 is unique among the mammalian ErbB receptors in being generally considered as kinase-inactive (6). When first cloned (7,8), amino acid substitutions were noted at two particular sites that are conserved in other known kinases (9). ...