scholarly journals CRI iAtlas: an interactive portal for immuno-oncology research

F1000Research ◽  
2020 ◽  
Vol 9 ◽  
pp. 1028
Author(s):  
James A. Eddy ◽  
Vésteinn Thorsson ◽  
Andrew E. Lamb ◽  
David L. Gibbs ◽  
Carolina Heimann ◽  
...  
Keyword(s):  
Digital Pathology ◽  
Driver Mutations ◽  
Immune Microenvironment ◽  
Cancer Driver ◽  
Tumor Subtypes ◽  
Oncology Research ◽  
Mutation Burden ◽  
Tumor Immune Microenvironment ◽  
Patient Responses ◽  
Tumor Types

The Cancer Research Institute (CRI) iAtlas is an interactive web platform for data exploration and discovery in the context of tumors and their interactions with the immune microenvironment. iAtlas allows researchers to study immune response characterizations and patterns for individual tumor types, tumor subtypes, and immune subtypes. iAtlas supports computation and visualization of correlations and statistics among features related to the tumor microenvironment, cell composition, immune expression signatures, tumor mutation burden, cancer driver mutations, adaptive cell clonality, patient survival, expression of key immunomodulators, and tumor infiltrating lymphocyte (TIL) spatial maps. iAtlas was launched to accompany the release of the TCGA PanCancer Atlas and has since been expanded to include new capabilities such as (1) user-defined loading of sample cohorts, (2) a tool for classifying expression data into immune subtypes, and (3) integration of TIL mapping from digital pathology images. We expect that the CRI iAtlas will accelerate discovery and improve patient outcomes by providing researchers access to standardized immunogenomics data to better understand the tumor immune microenvironment and its impact on patient responses to immunotherapy.

scholarly journals Genomic features and tumor immune microenvironment alteration in NSCLC treated with neoadjuvant PD-1 blockade

2022 ◽  
Vol 6 (1) ◽  
Author(s):  
Shuhang Wang ◽  
Pei Yuan ◽  
Beibei Mao ◽  
Ning Li ◽  
Jianming Ying ◽  
...  
Keyword(s):  
Copy Number ◽  
Copy Number Gain ◽  
Pathological Response ◽  
Immune Microenvironment ◽  
Tumor Mutation Burden ◽  
Neoadjuvant Immunotherapy ◽  
Mutation Burden ◽  
Tumor Immune Microenvironment ◽  
Nsclc Patients ◽  
Insight Into

AbstractSeveral clinical trials have shown the safety and effectiveness of PD-1/PD-L1 inhibitors in neoadjuvant therapy in resectable non-small cell lung cancer (NSCLC). However, 18–83% patients can benefit from it. In this study, we aimed to assess the association of PD-L1 expression, tumor mutation burden, copy number alteration (CNA, including copy number gain and loss) burden with the pathologic response to neoadjuvant PD-1 blockade and investigate the changes in the tumor immune microenvironment (TIME) during neoadjuvant immunotherapy in NSCLC. Pre-immunotherapy treatment tumor samples from twenty-nine NSCLC patients who received neoadjuvant immunotherapy with sintilimab, an anti-PD-1 drug, were subjected to targeted DNA sequencing and PD-L1 immunochemistry staining. The pathological response was positively correlated with tumor proportion score (TPS) of PD-L1 and negatively correlated with copy number gain (CNgain) burden. Of note, the combination of CNgain burden and TPS can better stratify major pathological response (MPR) patients than did CNgain or TPS alone. Whereas, TMB showed a limited correlation with pathological regression. Additionally, PD-1 blockade led to an increase in CD8+PD-1−T cells which was clinically relevant to MPR as evaluated by multiplex immunofluorescence. A significant reduction in CD19+ cells was observed in the Non-MPR group but not in the MPR group, indicating the involvement of B cells in improving neoadjuvant immunotherapy response in NSCLC. Together, our study provides new data for the correlation of PD-L1 expression and genomic factors with drug response in neoadjuvant immunotherapy settings in NSCLC. The changes of TIME may provide novel insight into the immune responses to neoadjuvant anti-PD-1 therapy.

scholarly journals Pathway and network analysis of more than 2,500 whole cancer genomes

2018 ◽  
Author(s):  
Matthew A. Reyna ◽  
David Haan ◽  
Marta Paczkowska ◽  
Lieven P.C. Verbeke ◽  
Miguel Vazquez ◽  
...  
Keyword(s):  
Rna Splicing ◽  
Driver Mutations ◽  
Cancer Genes ◽  
Protein Coding ◽  
Cancer Driver ◽  
Network Analyses ◽  
Protein Coding Genes ◽  
Cancer Genomes ◽  
Tumor Types ◽  
Promoter Mutations

AbstractThe catalog of cancer driver mutations in protein-coding genes has greatly expanded in the past decade. However, non-coding cancer driver mutations are less well-characterized and only a handful of recurrent non-coding mutations, most notablyTERTpromoter mutations, have been reported. Motivated by the success of pathway and network analyses in prioritizing rare mutations in protein-coding genes, we performed multi-faceted pathway and network analyses of non-coding mutations across 2,583 whole cancer genomes from 27 tumor types compiled by the ICGC/TCGA PCAWG project. While few non-coding genomic elements were recurrently mutated in this cohort, we identified 93 genes harboring non-coding mutations that cluster into several modules of interacting proteins. Among these are promoter mutations associated with reduced mRNA expression inTP53, TLE4, andTCF4. We found that biological processes had variable proportions of coding and non-coding mutations, with chromatin remodeling and proliferation pathways altered primarily by coding mutations, while developmental pathways, including Wnt and Notch, altered by both coding and non-coding mutations. RNA splicing was primarily targeted by non-coding mutations in this cohort, with samples containing non-coding mutations exhibiting similar gene expression signatures as coding mutations in well-known RNA splicing factors. These analyses contribute a new repertoire of possible cancer genes and mechanisms that are altered by non-coding mutations and offer insights into additional cancer vulnerabilities that can be investigated for potential therapeutic treatments.

scholarly journals Multiscale Agent-Based and Hybrid Modeling of the Tumor Immune Microenvironment

Processes ◽  
2019 ◽  
Vol 7 (1) ◽  
pp. 37 ◽  
Author(s):  
Kerri-Ann Norton ◽  
Chang Gong ◽  
Samira Jamalian ◽  
Aleksander Popel
Keyword(s):  
Immune Response ◽  
Tumor Heterogeneity ◽  
Computational Models ◽  
Digital Pathology ◽  
Hybrid Modeling ◽  
Immune Microenvironment ◽  
Agent Based ◽  
Tumor Immune Microenvironment ◽  
Cancer Tumor

Multiscale systems biology and systems pharmacology are powerful methodologies that are playing increasingly important roles in understanding the fundamental mechanisms of biological phenomena and in clinical applications. In this review, we summarize the state of the art in the applications of agent-based models (ABM) and hybrid modeling to the tumor immune microenvironment and cancer immune response, including immunotherapy. Heterogeneity is a hallmark of cancer; tumor heterogeneity at the molecular, cellular, and tissue scales is a major determinant of metastasis, drug resistance, and low response rate to molecular targeted therapies and immunotherapies. Agent-based modeling is an effective methodology to obtain and understand quantitative characteristics of these processes and to propose clinical solutions aimed at overcoming the current obstacles in cancer treatment. We review models focusing on intra-tumor heterogeneity, particularly on interactions between cancer cells and stromal cells, including immune cells, the role of tumor-associated vasculature in the immune response, immune-related tumor mechanobiology, and cancer immunotherapy. We discuss the role of digital pathology in parameterizing and validating spatial computational models and potential applications to therapeutics.

scholarly journals In silico saturation mutagenesis of cancer genes

2020 ◽  
Author(s):  
Ferran Muiños ◽  
Francisco Martinez-Jimenez ◽  
Oriol Pich ◽  
Abel Gonzalez-Perez ◽  
Nuria Lopez-Bigas
Keyword(s):  
In Silico ◽  
Tumor Development ◽  
Saturation Mutagenesis ◽  
Driver Mutations ◽  
Cancer Genes ◽  
Driver Genes ◽  
Cancer Driver ◽  
Mutation Probability ◽  
Tumor Types ◽  
Tumor Somatic Mutations

SummaryExtensive bioinformatics analysis of datasets of tumor somatic mutations data have revealed the presence of some 500-600 cancer driver genes. The identification of all potential driver mutations affecting cancer genes is essential to implement precision cancer medicine and to understand the interplay of mutation probability and selection in tumor development. Here, we present an in silico saturation mutagenesis approach to identify all driver mutations in 568 cancer genes across 66 tumor types. For most cancer genes the mutation probability across tissues --underpinned by active mutational processes-- influences which driver variants have been observed, although this differs significantly between tumor suppressor and oncogenes. The role of selection is apparent in some of the latter, the observed and unobserved driver mutations of which are equally likely to occur. The number of potential driver mutations in a cancer gene roughly determines how many mutations are available for detection across newly sequenced tumors.

scholarly journals Tumor Immune Microenvironment Landscape in Glioma Identifies a Prognostic and Immunotherapeutic Signature

2021 ◽  
Vol 9 ◽  
Author(s):  
Chunyu Zhang ◽  
Lirui Guo ◽  
Zhongzhou Su ◽  
Na Luo ◽  
Yinqiu Tan ◽  
...  
Keyword(s):  
Large Scale ◽  
The Cancer Genome Atlas ◽  
Immune Microenvironment ◽  
Mutation Burden ◽  
Tumor Immune Microenvironment ◽  
Cancer Genome Atlas ◽  
Patient Prognosis ◽  
Selection Operator ◽  
Cox Analysis ◽  
Genome Atlas

The tumor immune microenvironment (TIME) has been recognized to be associated with sensitivity to immunotherapy and patient prognosis. Recent research demonstrates that assessing the TIME patterns on large-scale samples will expand insights into TIME and will provide guidance to formulate immunotherapy strategies for tumors. However, until now, thorough research has not yet been reported on the immune infiltration landscape of glioma. Herein, the CIBERSORT algorithm was used to unveil the TIME landscape of 1,975 glioma observations. Three TIME subtypes were established, and the TIMEscore was calculated by least absolute shrinkage and selection operator (LASSO)–Cox analysis. The high TIMEscore was distinguished by an elevated tumor mutation burden (TMB) and activation of immune-related biological process, such as IL6-JAK-STAT3 signaling and interferon gamma (IFN-γ) response, which may demonstrate that the patients with high TIMEscore were more sensitive to immunotherapy. Multivariate analysis revealed that the TIMEscore could strongly and independently predict the prognosis of gliomas [Chinese Glioma Genome Atlas (CGGA) cohort: hazard ratio (HR): 2.134, p < 0.001; Gravendeel cohort: HR: 1.872, p < 0.001; Kamoun cohort: HR: 1.705, p < 0.001; The Cancer Genome Atlas (TCGA) cohort: HR: 2.033, p < 0.001; the combined cohort: HR: 1.626, p < 0.001], and survival advantage was evident among those who received chemotherapy. Finally, we validated the performance of the signature in human tissues from Wuhan University (WHU) dataset (HR: 15.090, p = 0.008). Our research suggested that the TIMEscore could be applied as an effective predictor for adjuvant therapy and prognosis assessment.

Identifying GNG4 might play an important role in colorectal cancer TMB

2021 ◽  
pp. 1-16
Author(s):  
Hongcan Zhao ◽  
Sheng Danli ◽  
Ze Qian ◽  
Sunyi Ye ◽  
Jianzhong Chen ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Liver Metastases ◽  
Genomic Analysis ◽  
Recurrence Risk ◽  
Computational Method ◽  
The Cancer Genome Atlas ◽  
Immune Microenvironment ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Tumor Immune Microenvironment

BACKGROUND: Colorectal carcinoma (CRC) is one of the most leading cause of cancer death all over the world. The tumor immune microenvironment is illustrated to be necessary for the progress of CRC. And the accumulating evidence indicated that tumor mutation burden (TMB) is effective in differentiating responding population of immune checkpoint inhibitor (ICI) therapies in various cancers. In this study, we aimed to evaluated the potential relationship between TMB and the recurrence risk of CRC. METHODS: The transcriptomic and clinical data of CRC patients were collected from The Cancer Genome Atlas (TCGA) database (n= 382). Then the genomic analysis of tumor mutation burden and tumor purity were conducted by a computational method based on transcriptomic data. RESULTS: Firstly, we accessed the distribution of TMB and preferences at the gene and mutation level using somatic mutation data from TCGA data about CRC. We identified that high TMB predicted better prognosis of CRC patients. Secondly, the differentially expressed genes (DEGs) between the low TMB and high TMB group was clarified. Then the protein-protein interaction (PPI) analysis was performed, and the results confirmed ten hub genes among the DEGs. Utilizing the GEPIA web-tool, we discovered that GNG4 was up-regulated in tumor tissues, and GNG4 was related to the overall survival (OS) and tumor free survival (TFS) of CRC patients. Therefore, we considered GNG4 was essential for the tumor immune microenvironment of CRC. Furthermore, we also accessed the protein level of GNG4 in CRC and liver metastases from CRC. CONCLUSIONS: In this study, GNG4 was demonstrated to be the key element of the CRC TMB, which will be essential for the ICI therapy of CRC. Besides, GNG4 was up-regulated in CRC and liver metastases from CRC tissues. Thus, we thought that GNG4 might play an important role in colorectal cancer TMB and induce its metastasis in liver.

scholarly journals Priming the tumor immune microenvironment with chemo(radio)therapy: A systematic review across tumor types

2020 ◽  
Vol 1874 (1) ◽  
pp. 188386 ◽  
Author(s):  
Tom van den Ende ◽  
Héctor G. van den Boorn ◽  
Nadine M. Hoonhout ◽  
Faridi S. van Etten-Jamaludin ◽  
Sybren L. Meijer ◽  
...  
Keyword(s):  
Systematic Review ◽  
Immune Microenvironment ◽  
Radio Therapy ◽  
Tumor Immune Microenvironment ◽  
Tumor Types

scholarly journals Heparanase (HPSE) Associates with the Tumor Immune Microenvironment in Colorectal Cancer

Processes ◽  
2021 ◽  
Vol 9 (9) ◽  
pp. 1605
Author(s):  
Mengling Liu ◽  
Qing Liu ◽  
Yitao Yuan ◽  
Suyao Li ◽  
Yu Dong ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarkers ◽  
Positive Association ◽  
Immune Microenvironment ◽  
High Expression Group ◽  
Mutation Burden ◽  
Tumor Immune Microenvironment ◽  
Public Datasets

There is an unmet clinical need to identify potential predictive biomarkers for immunotherapy efficacy in mismatch repair proficient (pMMR) metastatic colorectal cancer (mCRC). Heparanase (HPSE) is a multifunctional molecule mediating tumor–host crosstalk. However, the function of HPSE in the tumor immune microenvironment of CRC remains unclear. Data of CRC patients from public datasets (TCGA and GSE39582) and Zhongshan Hospital (ZS cohort) were collected to perform integrative bioinformatic analyses. In total, 1036 samples from TCGA (N = 457), GSE39582 (N = 510) and ZS cohort (N = 69) were included. Samples of deficient MMR (dMMR) and consensus molecular subtypes 1 (CMS1) showed significantly higher HPSE expression. The expression of HPSE also exhibited a significantly positive association with PD-L1 expression, tumor mutation burden and the infiltration of macrophages. Immune pathways were remarkably enriched in the HPSE high-expression group, which also showed higher expressions of chemokines and immune checkpoint genes. Survival analysis suggested that high HPSE expression tended to be associated with shorter overall survival in patients with pMMR mCRC. HPSE might contribute to the immune-activated tumor microenvironment with high levels of immune checkpoint molecules, suggesting that pMMR mCRC with high HPSE expression might respond to immune checkpoint inhibitors.

NIR-active Nanoterminator with Mature Dendritic Cell Acitivities for Immuno-Priming Mild Photothermal Cancer Therapy

2020 ◽  
Author(s):  
zhihong sun ◽  
Guanjun Deng ◽  
Xinghua Peng ◽  
Xiuli Xu ◽  
Lanlan Liu ◽  
...  
Keyword(s):  
Dendritic Cell ◽  
Photothermal Therapy ◽  
Whole Body ◽  
Mature Dendritic Cell ◽  
Immune Microenvironment ◽  
Highly Efficient ◽  
Tumor Immune Microenvironment ◽  
Shock Proteins ◽  
Mild Temperature ◽  
Broad Interest

Recently, photothermal-immuno synergistic therapy under mild temperature (~ 45 °C) has got broad interest in cancer treatment. Inhibition the intratumorally HSPs production is the key to accomplish highly efficient and mild photothermal therapy. In this work, we developed biomimetic nanoterminators with mature DCs functions by coating the mature dendritic cell membrane on photothermal nanoagents. As-prepared nanoterminators could automatically locate on T cell in the complex tumor-immune microenvironment and promote the T cells proliferation, activation and cytokine secretion, which could not only inhibit the expression of heat shock proteins to cooperate on highly efficient mild photothermal therapy (~42°C), but also promote tumor apoptosis during the treatment. More importantly, this nanoterminator could serve as vaccine to trigger anti-tumor immune response of the whole body, which would be promising to long-life tumor inhibition and termination.

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