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      TIMER2.0 for analysis of tumor-infiltrating immune cells

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          Abstract

          Tumor progression and the efficacy of immunotherapy are strongly influenced by the composition and abundance of immune cells in the tumor microenvironment. Due to the limitations of direct measurement methods, computational algorithms are often used to infer immune cell composition from bulk tumor transcriptome profiles. These estimated tumor immune infiltrate populations have been associated with genomic and transcriptomic changes in the tumors, providing insight into tumor–immune interactions. However, such investigations on large-scale public data remain challenging. To lower the barriers for the analysis of complex tumor–immune interactions, we significantly improved our previous web platform TIMER. Instead of just using one algorithm, TIMER2.0 ( http://timer.cistrome.org/) provides more robust estimation of immune infiltration levels for The Cancer Genome Atlas (TCGA) or user-provided tumor profiles using six state-of-the-art algorithms. TIMER2.0 provides four modules for investigating the associations between immune infiltrates and genetic or clinical features, and four modules for exploring cancer-related associations in the TCGA cohorts. Each module can generate a functional heatmap table, enabling the user to easily identify significant associations in multiple cancer types simultaneously. Overall, the TIMER2.0 web server provides comprehensive analysis and visualization functions of tumor infiltrating immune cells.

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          Most cited references8

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          Molecular and pharmacological modulators of the tumor immune contexture revealed by deconvolution of RNA-seq data

          We introduce quanTIseq, a method to quantify the fractions of ten immune cell types from bulk RNA-sequencing data. quanTIseq was extensively validated in blood and tumor samples using simulated, flow cytometry, and immunohistochemistry data. quanTIseq analysis of 8000 tumor samples revealed that cytotoxic T cell infiltration is more strongly associated with the activation of the CXCR3/CXCL9 axis than with mutational load and that deconvolution-based cell scores have prognostic value in several solid cancers. Finally, we used quanTIseq to show how kinase inhibitors modulate the immune contexture and to reveal immune-cell types that underlie differential patients’ responses to checkpoint blockers. Availability: quanTIseq is available at http://icbi.at/quantiseq. Electronic supplementary material The online version of this article (10.1186/s13073-019-0638-6) contains supplementary material, which is available to authorized users.
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            Large-scale public data reuse to model immunotherapy response and resistance

            Despite growing numbers of immune checkpoint blockade (ICB) trials with available omics data, it remains challenging to evaluate the robustness of ICB response and immune evasion mechanisms comprehensively. To address these challenges, we integrated large-scale omics data and biomarkers on published ICB trials, non-immunotherapy tumor profiles, and CRISPR screens on a web platform TIDE (http://tide.dfci.harvard.edu). We processed the omics data for over 33K samples in 188 tumor cohorts from public databases, 998 tumors from 12 ICB clinical studies, and eight CRISPR screens that identified gene modulators of the anticancer immune response. Integrating these data on the TIDE web platform with three interactive analysis modules, we demonstrate the utility of public data reuse in hypothesis generation, biomarker optimization, and patient stratification.
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              Quantifying tumor-infiltrating immune cells from transcriptomics data

              By exerting pro- and anti-tumorigenic actions, tumor-infiltrating immune cells can profoundly influence tumor progression, as well as the success of anti-cancer therapies. Therefore, the quantification of tumor-infiltrating immune cells holds the promise to unveil the multi-faceted role of the immune system in human cancers and its involvement in tumor escape mechanisms and response to therapy. Tumor-infiltrating immune cells can be quantified from RNA sequencing data of human tumors using bioinformatics approaches. In this review, we describe state-of-the-art computational methods for the quantification of immune cells from transcriptomics data and discuss the open challenges that must be addressed to accurately quantify immune infiltrates from RNA sequencing data of human bulk tumors. Electronic supplementary material The online version of this article (10.1007/s00262-018-2150-z) contains supplementary material, which is available to authorized users.
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                Author and article information

                Contributors
                Journal
                Nucleic Acids Res
                Nucleic Acids Res
                nar
                Nucleic Acids Research
                Oxford University Press
                0305-1048
                1362-4962
                02 July 2020
                22 May 2020
                22 May 2020
                : 48
                : W1
                : W509-W514
                Affiliations
                State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University , Chengdu, Sichuan 610041, China
                Department of Data Sciences, Dana Farber Cancer Institute, Harvard T.H. Chan School of Public Health , Boston, MA 02215, USA
                Clinical Translational Research Center, Shanghai Pulmonary Hospital, School of Life Science and Technology, Tongji University , Shanghai 200433, China
                Department of Data Sciences, Dana Farber Cancer Institute, Harvard T.H. Chan School of Public Health , Boston, MA 02215, USA
                Department of Data Sciences, Dana Farber Cancer Institute, Harvard T.H. Chan School of Public Health , Boston, MA 02215, USA
                State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University , Chengdu, Sichuan 610041, China
                State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University , Chengdu, Sichuan 610041, China
                Lyda Hill Department of Bioinformatics, The University of Texas Southwestern Medical Center , Dallas, TX 75390, USA
                Department of Data Sciences, Dana Farber Cancer Institute, Harvard T.H. Chan School of Public Health , Boston, MA 02215, USA
                Author notes
                To whom correspondence should be addressed. Tel: +1 617 632 2472; Fax: +1 617 632 2444; Email: xsliu@ 123456ds.dfci.harvard.edu

                The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.

                Author information
                http://orcid.org/0000-0001-7940-8196
                http://orcid.org/0000-0003-4736-7339
                Article
                gkaa407
                10.1093/nar/gkaa407
                7319575
                32442275
                fcb186f4-bb26-44c2-9987-f07b8c2dff88
                © The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@ 123456oup.com

                History
                : 17 May 2020
                : 26 April 2020
                : 09 March 2020
                Page count
                Pages: 6
                Funding
                Funded by: National Institutes of Health, DOI 10.13039/100000002;
                Funded by: National Natural Science Foundation of China, DOI 10.13039/501100001809;
                Award ID: 81972551
                Award ID: 81702701
                Award ID: 81520108009
                Award ID: B14038
                Funded by: Cancer Prevention and Research Institute of Texas, DOI 10.13039/100004917;
                Award ID: RR170079
                Categories
                AcademicSubjects/SCI00010
                Web Server Issue

                Genetics
                Genetics

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