TIMER: A Web Server for Comprehensive Analysis of Tumor-Infiltrating Immune Cells
TL;DR: Tumor Immune Estimation Resource (TIMER) is presented to comprehensively investigate molecular characterization of tumor-immune interactions and provides a user-friendly web interface for dynamic analysis and visualization of these associations, which will be of broad utilities to cancer researchers.
Abstract: Recent clinical successes of cancer immunotherapy necessitate the investigation of the interaction between malignant cells and the host immune system. However, elucidation of complex tumor-immune interactions presents major computational and experimental challenges. Here, we present Tumor Immune Estimation Resource (TIMER; cistrome.shinyapps.io/timer) to comprehensively investigate molecular characterization of tumor-immune interactions. Levels of six tumor-infiltrating immune subsets are precalculated for 10,897 tumors from 32 cancer types. TIMER provides 6 major analytic modules that allow users to interactively explore the associations between immune infiltrates and a wide spectrum of factors, including gene expression, clinical outcomes, somatic mutations, and somatic copy number alterations. TIMER provides a user-friendly web interface for dynamic analysis and visualization of these associations, which will be of broad utilities to cancer researchers. Cancer Res; 77(21); e108-10. ©2017 AACR.
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TL;DR: 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.
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.
1,992 citations
Cites methods from "TIMER: A Web Server for Comprehensi..."
...This motivated us to improve TIMER, a web server that we developed previously (14)....
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...The original TIMER web server included only one immune infiltration estimation algorithm (14)....
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TL;DR: A panel of therapeutic strategies to use, combine and develop to treat hot, altered and cold tumours is provided and the impact of combination therapy on the immune response to convert an immune cold into a hot tumour will be discussed.
Abstract: Immunotherapies are the most rapidly growing drug class and have a major impact in oncology and on human health. It is increasingly clear that the effectiveness of immunomodulatory strategies depends on the presence of a baseline immune response and on unleashing of pre-existing immunity. Therefore, a general consensus emerged on the central part played by effector T cells in the antitumour responses. Recent technological, analytical and mechanistic advances in immunology have enabled the identification of patients who are more likely to respond to immunotherapy. In this Review, we focus on defining hot, altered and cold tumours, the complexity of the tumour microenvironment, the Immunoscore and immune contexture of tumours, and we describe approaches to treat such tumours with combination immunotherapies, including checkpoint inhibitors. In the upcoming era of combination immunotherapy, it is becoming critical to understand the mechanisms responsible for hot, altered or cold immune tumours in order to boost a weak antitumour immunity. The impact of combination therapy on the immune response to convert an immune cold into a hot tumour will be discussed.
1,680 citations
TL;DR: This review summarizes knowledge of the reciprocal interaction between antitumor immunity and distinct cell death mechanisms, particularly necroptosis, ferroPTosis, and pyroaptosis, which are the three potentially novel mechanisms of immunogenic cell death.
Abstract: In recent years, cancer immunotherapy based on immune checkpoint inhibitors (ICIs) has achieved considerable success in the clinic. However, ICIs are significantly limited by the fact that only one third of patients with most types of cancer respond to these agents. The induction of cell death mechanisms other than apoptosis has gradually emerged as a new cancer treatment strategy because most tumors harbor innate resistance to apoptosis. However, to date, the possibility of combining these two modalities has not been discussed systematically. Recently, a few studies revealed crosstalk between distinct cell death mechanisms and antitumor immunity. The induction of pyroptosis, ferroptosis, and necroptosis combined with ICIs showed synergistically enhanced antitumor activity, even in ICI-resistant tumors. Immunotherapy-activated CD8+ T cells are traditionally believed to induce tumor cell death via the following two main pathways: (i) perforin-granzyme and (ii) Fas-FasL. However, recent studies identified a new mechanism by which CD8+ T cells suppress tumor growth by inducing ferroptosis and pyroptosis, which provoked a review of the relationship between tumor cell death mechanisms and immune system activation. Hence, in this review, we summarize knowledge of the reciprocal interaction between antitumor immunity and distinct cell death mechanisms, particularly necroptosis, ferroptosis, and pyroptosis, which are the three potentially novel mechanisms of immunogenic cell death. Because most evidence is derived from studies using animal and cell models, we also reviewed related bioinformatics data available for human tissues in public databases, which partially confirmed the presence of interactions between tumor cell death and the activation of antitumor immunity.
576 citations
TL;DR: Application of ImmuCellAI to immunotherapy datasets reveals that the abundance of dendritic cells, cytotoxic T, and gamma delta T cells is significantly higher both in comparisons of on‐treatment versus pre‐treatment and responders versus non‐responders.
Abstract: The distribution and abundance of immune cells, particularly T-cell subsets, play pivotal roles in cancer immunology and therapy. T cells have many subsets with specific function and current methods are limited in estimating them, thus, a method for predicting comprehensive T-cell subsets is urgently needed in cancer immunology research. Here, Immune Cell Abundance Identifier (ImmuCellAI), a gene set signature-based method, is introduced for precisely estimating the abundance of 24 immune cell types including 18 T-cell subsets, from gene expression data. Performance evaluation on both the sequencing data with flow cytometry results and public expression data indicate that ImmuCellAI can estimate the abundance of immune cells with superior accuracy to other methods especially on many T-cell subsets. Application of ImmuCellAI to immunotherapy datasets reveals that the abundance of dendritic cells, cytotoxic T, and gamma delta T cells is significantly higher both in comparisons of on-treatment versus pre-treatment and responders versus non-responders. Meanwhile, an ImmuCellAI result-based model is built for predicting the immunotherapy response with high accuracy (area under curve 0.80-0.91). These results demonstrate the powerful and unique function of ImmuCellAI in tumor immune infiltration estimation and immunotherapy response prediction.
459 citations
TL;DR: In this paper, 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.
Abstract: 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.
259 citations
References
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TL;DR: Preliminary clinical findings with blockers of additional immune-checkpoint proteins, such as programmed cell death protein 1 (PD1), indicate broad and diverse opportunities to enhance antitumour immunity with the potential to produce durable clinical responses.
Abstract: Immune checkpoints refer to the plethora of inhibitory pathways that are crucial to maintaining self-tolerance. Tumour cells induce immune checkpoints to evade immunosurveillance. This Review discusses the progress in targeting immune checkpoints, the considerations for combinatorial therapy and the potential for additional immune-checkpoint targets.
10,602 citations
"TIMER: A Web Server for Comprehensi..." refers background in this paper
...Recent advances in immunotherapy, especially checkpoint blockade, have resulted in clinical success in treating late-stage cancers (1)....
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TL;DR: CIBERSORT outperformed other methods with respect to noise, unknown mixture content and closely related cell types when applied to enumeration of hematopoietic subsets in RNA mixtures from fresh, frozen and fixed tissues, including solid tumors.
Abstract: We introduce CIBERSORT, a method for characterizing cell composition of complex tissues from their gene expression profiles When applied to enumeration of hematopoietic subsets in RNA mixtures from fresh, frozen and fixed tissues, including solid tumors, CIBERSORT outperformed other methods with respect to noise, unknown mixture content and closely related cell types CIBERSORT should enable large-scale analysis of RNA mixtures for cellular biomarkers and therapeutic targets (http://cibersortstanfordedu/)
6,967 citations
"TIMER: A Web Server for Comprehensi..." refers methods in this paper
...One influential deconvolution method, CIBERSORT, utilizes microarray data with a predefined immune signature matrix to estimate the fraction of 22 tumor-infiltrating immune cells (TIIC) within a given sample (5)....
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TL;DR: In this Opinion article, the context-specific nature of infiltrating immune cells can affect the prognosis of patients is discussed.
Abstract: Tumours grow within an intricate network of epithelial cells, vascular and lymphatic vessels, cytokines and chemokines, and infiltrating immune cells. Different types of infiltrating immune cells have different effects on tumour progression, which can vary according to cancer type. In this Opinion article we discuss how the context-specific nature of infiltrating immune cells can affect the prognosis of patients.
3,759 citations
"TIMER: A Web Server for Comprehensi..." refers background in this paper
...Survival module Many studies have reported a prominent impact of TIICs on clinical outcome of cancer patients (11)....
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TL;DR: The genetic findings provide evidence for immunoediting in tumors and uncover mechanisms of tumor-intrinsic resistance to cytolytic activity, suggesting immune-mediated elimination.
2,600 citations
"TIMER: A Web Server for Comprehensi..." refers methods in this paper
...One seminal study measures effector cell cytolytic activity using the transcript levels of two genes, GZMA and PRF1, to elucidate possible mechanisms of immune evasion (8)....
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TL;DR: By separating SCNA profiles into underlying arm-level and focal alterations, the estimation of background rates for each category is improved, and a probabilistic method for defining the boundaries of selected-for SCNA regions with user-defined confidence is described.
Abstract: We describe methods with enhanced power and specificity to identify genes targeted by somatic copy-number alterations (SCNAs) that drive cancer growth. By separating SCNA profiles into underlying arm-level and focal alterations, we improve the estimation of background rates for each category. We additionally describe a probabilistic method for defining the boundaries of selected-for SCNA regions with user-defined confidence. Here we detail this revised computational approach, GISTIC2.0, and validate its performance in real and simulated datasets.
2,392 citations
"TIMER: A Web Server for Comprehensi..." refers background in this paper
...0 (14), including deep deletion, shallow deletion, diploid/normal, lowlevel gain, andhigh amplification....
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