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      xCell: digitally portraying the tissue cellular heterogeneity landscape

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      Genome Biology
      BioMed Central

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          Abstract

          Tissues are complex milieus consisting of numerous cell types. Several recent methods have attempted to enumerate cell subsets from transcriptomes. However, the available methods have used limited sources for training and give only a partial portrayal of the full cellular landscape. Here we present xCell, a novel gene signature-based method, and use it to infer 64 immune and stromal cell types. We harmonized 1822 pure human cell type transcriptomes from various sources and employed a curve fitting approach for linear comparison of cell types and introduced a novel spillover compensation technique for separating them. Using extensive in silico analyses and comparison to cytometry immunophenotyping, we show that xCell outperforms other methods. xCell is available at http://xCell.ucsf.edu/.

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          The online version of this article (doi:10.1186/s13059-017-1349-1) contains supplementary material, which is available to authorized users.

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          Pan-cancer Immunogenomic Analyses Reveal Genotype-Immunophenotype Relationships and Predictors of Response to Checkpoint Blockade.

          The Cancer Genome Atlas revealed the genomic landscapes of human cancers. In parallel, immunotherapy is transforming the treatment of advanced cancers. Unfortunately, the majority of patients do not respond to immunotherapy, making the identification of predictive markers and the mechanisms of resistance an area of intense research. To increase our understanding of tumor-immune cell interactions, we characterized the intratumoral immune landscapes and the cancer antigenomes from 20 solid cancers and created The Cancer Immunome Atlas (https://tcia.at/). Cellular characterization of the immune infiltrates showed that tumor genotypes determine immunophenotypes and tumor escape mechanisms. Using machine learning, we identified determinants of tumor immunogenicity and developed a scoring scheme for the quantification termed immunophenoscore. The immunophenoscore was a superior predictor of response to anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) and anti-programmed cell death protein 1 (anti-PD-1) antibodies in two independent validation cohorts. Our findings and this resource may help inform cancer immunotherapy and facilitate the development of precision immuno-oncology.
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            The Ensembl Variant Effect Predictor

            The Ensembl Variant Effect Predictor is a powerful toolset for the analysis, annotation, and prioritization of genomic variants in coding and non-coding regions. It provides access to an extensive collection of genomic annotation, with a variety of interfaces to suit different requirements, and simple options for configuring and extending analysis. It is open source, free to use, and supports full reproducibility of results. The Ensembl Variant Effect Predictor can simplify and accelerate variant interpretation in a wide range of study designs.
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              Immunological hallmarks of stromal cells in the tumour microenvironment.

              A dynamic and mutualistic interaction between tumour cells and the surrounding stroma promotes the initiation, progression, metastasis and chemoresistance of solid tumours. Far less understood is the relationship between the stroma and tumour-infiltrating leukocytes; however, emerging evidence suggests that the stromal compartment can shape antitumour immunity and responsiveness to immunotherapy. Thus, there is growing interest in elucidating the immunomodulatory roles of the stroma that evolve within the tumour microenvironment. In this Review, we discuss the evidence that stromal determinants interact with leukocytes and influence antitumour immunity, with emphasis on the immunological attributes of stromal cells that may foster their protumorigenic function.
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                Author and article information

                Contributors
                dvir.aran@ucsf.edu
                zicheng.hu@ucsf.edu
                (415) 514-0528 , atul.butte@ucsf.edu
                Journal
                Genome Biol
                Genome Biol
                Genome Biology
                BioMed Central (London )
                1474-7596
                1474-760X
                15 November 2017
                15 November 2017
                2017
                : 18
                : 220
                Affiliations
                ISNI 0000 0001 2297 6811, GRID grid.266102.1, Institute for Computational Health Sciences, , University of California, ; San Francisco, California 94158 USA
                Author information
                http://orcid.org/0000-0002-7433-2740
                Article
                1349
                10.1186/s13059-017-1349-1
                5688663
                29141660
                26274613-9816-4cad-a3b6-9bbf7b1a2e3b
                © The Author(s). 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 6 March 2017
                : 10 October 2017
                Funding
                Funded by: National Cancer Institute (US)
                Award ID: U24 CA195858
                Award Recipient :
                Funded by: Division of Intramural Research, National Institute of Allergy and Infectious Diseases (US)
                Award ID: HHSN272201200028C
                Award Recipient :
                Funded by: Gruss Lipper Postdoctoral Fellowship
                Categories
                Method
                Custom metadata
                © The Author(s) 2017

                Genetics
                Genetics

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