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Immunotherapy using dendritic cell （DC）-based vaccination is an approved approach for harnessing the potential of a patient＇s own immune system to eliminate tumor cells in metastatic hormone-refractory cancer. Overall, al- though many DC vaccines have been tested in the clinic and proven to be immunogenic, and in some cases associated with clinical outcome, there remains no consensus on how to manufacture DC vaccines. In this review we will discuss what has been learned thus far about human DC biology from clinical studies, and how current approaches to apply DC vaccines in the clinic could be improved to enhance anti-tumor immunity.

Potent dendritic-cell cancer vaccines could be used to induce functional antitumour immunity without off-target toxicity.

GRavitational lEnsing Accuracy Testing 2010 (GREAT10) is a public image analysis challenge aimed at the development of algorithms to analyze astronomical images. Specifically, the challenge is to measure varying image distortions in the presence of a variable convolution kernel, pixelization and noise. This is the second in a series of challenges set to the astronomy, computer science and statistics communities, providing a structured environment in which methods can be improved and tested in preparation for planned astronomical surveys. GREAT10 extends upon previous work by introducing variable fields into the challenge. The \"Galaxy Challenge\" involves the precise measurement of galaxy shape distortions, quantified locally by two parameters called shear, in the presence of a known convolution kernel. Crucially, the convolution kernel and the simulated gravitational lensing shape distortion both now vary as a function of position within the images, as is the case for real data. In addition, we introduce the \"Star Challenge\" that concerns the reconstruction of a variable convolution kernel, similar to that in a typical astronomical observation. This document details the GREAT10 Challenge for potential participants. Continually updated information is also available from www.greatchallenges.info.

The GRavitational lEnsing Accuracy Testing 2008 (GREAT08) Challenge focuses on a problem that is of crucial importance for future observations in cosmology. The shapes of distant galaxies can be used to determine the properties of dark energy and the nature of gravity, because light from those galaxies is bent by gravity from the intervening dark matter. The observed galaxy images appear distorted, although only slightly, and their shapes must be precisely disentangled from the effects of pixelisation, convolution and noise. The worldwide gravitational lensing community has made significant progress in techniques to measure these distortions via the Shear TEsting Program (STEP). Via STEP, we have run challenges within our own community, and come to recognise that this particular image analysis problem is ideally matched to experts in statistical inference, inverse problems and computational learning. Thus, in order to continue the progress seen in recent years, we are seeking an infusion of new ideas from these communities. This document details the GREAT08 Challenge for potential participants. Please visit www.great08challenge.info for the latest information.

Maturation of conventional dendritic cells (cDCs) is crucial for maintaining tolerogenic safeguards against auto-immunity and for promoting immunogenic responses to pathogens and cancer. The subcellular mechanism for cDC maturation remains poorly defined. We show that cDCs mature by leveraging an internal reservoir of cholesterol (harnessed from extracellular cell debris and generated by de novo synthesis) to assemble lipid nanodomains on cell surfaces of maturing cDCs, enhance expression of maturation markers and stabilize immune receptor signaling. This process is dependent on cholesterol transport through Niemann–Pick disease type C1 (NPC1) and mediates homeostatic and Toll-like receptor (TLR)-induced maturation. Importantly, we identified the receptor tyrosine kinase AXL as a regulator of the NPC1-dependent construction of lipid nanodomains. Deleting AXL from cDCs enhances their maturation, thus improving anti-tumor immunity. Altogether, our study presents new insights into cholesterol mobilization as a fundamental basis for cDC maturation and highlights AXL as a therapeutic target for modulating cDCs. To mature, dendritic cells collect and synthesize cholesterol to construct lipid nanodomains on their membranes. Obstructing this process impairs their ability to prime T cells.

Generating responses to tumor antigens poses a challenge for immunotherapy. This phase II trial (NCT02129075) tested fms-like tyrosine kinase 3 (Flt3) ligand pre-treatment enhancement of responses to dendritic cell (DC)-targeting vaccines. We evaluated a regimen of Flt3L (CDX-301) to increase DCs and other antigen-presenting cells, poly-ICLC (TLR3 agonist that activates DCs) and a vaccine comprising anti-DEC-205-NY-ESO-1, a fusion antibody targeting CD205, linked to NY-ESO-1. High-risk melanoma patients were randomized to vaccine, with and without CDX-301. The end point was immune response to NY-ESO-1. Flt3L increased peripheral monocytes and conventional DCs (cDCs), including cross-presenting cDC1 and cDC2 and plasmacytoid DCs. Significant increases in humoral and T-cell responses and activation of DCs, natural killer cells and T cells were elicited. Transcriptional analyses revealed gene signatures associated with CDX-301 induction of an early, durable immune response. This study reveals in vivo effects of Flt3L on innate immune cells in the setting of vaccination, leading to an immunogenic vaccine regimen.

Neoantigen-targeted immunotherapies hold promise for cancer treatment, but current personalized approaches are time-consuming and costly. Here, we identify neoantigens encoded by and that are shared across murine mismatch repair-deficient colorectal and breast tumors and unexpectedly conserved in human colorectal, endometrial, gastric, and prostate cancers. These neoantigens elicit spontaneous, organ-spanning CD8+ T cell-mediated memory responses that are enhanced by immune checkpoint blockade. Vaccination with mRNA/lipid nanoparticles encoding these conserved neoantigens suppresses tumor growth across prophylactic and therapeutic models, including checkpoint-resistant orthotopic tumors. Tumor rejection is accompanied by antigen spreading, abscopal effects, and infiltration by clonally diverse T cells, dendritic cells, and MHC I/II+ macrophages producing CXCL9/10, CCL5/8, and TNF. Tumor cells also show activation of innate and adaptive pathways, including MHC and ISGs overexpression. Our results uncover a conserved anti-tumor immune mechanism and support the development of off-the-shelf neoantigen vaccines across tissues and species.

NK cells are innate lymphocytes critical for surveillance of viruses and tumors, however the mechanisms underlying NK cell dysfunction in cancer are incompletely understood. We assessed the effector function of NK cells from bladder cancer patients and found severe dysfunction in NK cells derived from tumors versus peripheral blood. While both peripheral and tumor-infiltrating NK cells exhibited conserved patterns of inhibitory receptor over-expression, this did not explain the observed defects in NK surveillance in bladder tumors. Rather, TME-specific TGF-β and metabolic perturbations such as hypoxia directly suppressed NK cell function. Specifically, an oxygen-dependent reduction in signaling through SLAMF6 was mechanistically responsible for poor NK cell function, as tumor-infiltrating NK cells cultured under normoxic conditions exhibited complete restoration of function, while deletion of SLAMF6 abrogated NK cell cytolytic function even under normoxic conditions. Collectively, this work highlights the role of tissue-specific factors in dictating NK cell function, and implicates SLAMF6 signaling as a rational target for immuno-modulation to improve NK cell function in bladder cancer.

We present a method of calibrating the properties of photometric redshift bins as part of a larger Markov Chain Monte Carlo (MCMC) analysis for the inference of cosmological parameters. The redshift bins are characterised by their mean and variance, which are varied as free parameters and marginalised over when obtaining the cosmological parameters. We demonstrate that the likelihood function for cross-correlations in an angular power spectrum framework tightly constrains the properties of bins such that they may be well determined, reducing their influence on cosmological parameters and avoiding the bias from poorly estimated redshift distributions. We demonstrate that even with only three photometric and three spectroscopic bins, we can recover accurate estimates of the mean redshift of a bin to within \\(\\Delta\\mu \\approx 3-4 \\times10^{-3}\\) and the width of the bin to \\(\\Delta\\sigma \\approx 1\\times10^{-3}\\) for galaxies near \\(z = 1\\). This indicates that we may be able to bring down the photometric redshift errors to a level which is in line with the requirements for the next generation of cosmological experiments.