scholarly journals M6a Regulator-Associated Methylation Modification Patterns Shape Tumor Microenvironment Characteristics in Hepatocellular Carcinoma

2021 ◽  
Author(s):  
Bobin Ning ◽  
Yonggan Xue ◽  
Hongyi Liu ◽  
Hongyu Sun ◽  
Baoqing Jia
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Microenvironment ◽  
Single Cell ◽  
Signaling Pathways ◽  
Principal Component ◽  
Unsupervised Clustering ◽  
Survival Prediction ◽  
Multiple Perspectives ◽  
Single Cell Sequencing ◽  
Survival Expectations

Abstract Although substantial achievements in the tumor microenvironment (TME) of hepatocellular carcinoma (HCC) have led to fundamental improvements both in the basic research and clinical management, the potential mechanisms and regulatory relationships between m6A regulators and the TME are still unknown. We first conducted unsupervised clustering on the samples according to the core m6A expression, and then compared the signaling pathways, differential genes (DEGs), and TME between the m6A phenotypes, and re-validated the relationship between m6A regulators and TME by single cell sequencing. Then, the geneCluster was obtained by another unsupervised clustering of the DEGs, and the clinical as well as TME traits were evaluated among the geneClusters. Finally, the m6A scores of individual patients were calculated by principal component analysis (PCA) to verify the correlation from multiple perspectives, including survivals, clinical characters, mutations, TME, immunotherapy, and chemotherapy. Through a comprehensive analysis of 729 samples, we classified HCC patients into three m6A clusters and three geneClusters. Each group exhibited remarkable variations in terms of signaling pathways, clinical traits, and survival expectations. Notably, the m6A phenotypes corresponded to three different types of TME, namely immune-inflamed, immune-excluded, and immune-desert, respectively. In addition, the m6A regulator can accurately reflect the individualized microenvironment in HCC, and present supreme expression levels in the stromal microenvironment. However, the m6A score system is able to make accurate predictions not only in terms of clinical traits, survival prediction, and TME mentioned above, but also in the sensitivity of HCC patients to immunotherapy and chemotherapy. This study revealed the uniqueness and pluripotency of m6A regulators in the TME of HCC by combining single-cell sequencing and bulk sequencing. The quantified m6A modification indices were able to accurately predict patient survival expectations, clinical traits, TME, and sensitivity to immunotherapy and chemotherapy.

scholarly journals From Oncogenic Signaling Pathways to Single-Cell Sequencing of Immune Cells: Changing the Landscape of Cancer Immunotherapy

Molecules ◽  
2021 ◽  
Vol 26 (8) ◽  
pp. 2278
Author(s):  
Afshin Derakhshani ◽  
Zeinab Rostami ◽  
Hossein Safarpour ◽  
Mahdi Abdoli Shadbad ◽  
Niloufar Sadat Nourbakhsh ◽  
...  
Keyword(s):  
Single Cell ◽  
Signaling Pathways ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Cancer Development ◽  
Immune Checkpoints ◽  
Single Cell Sequencing ◽  
Increased Risk

Over the past decade, there have been remarkable advances in understanding the signaling pathways involved in cancer development. It is well-established that cancer is caused by the dysregulation of cellular pathways involved in proliferation, cell cycle, apoptosis, cell metabolism, migration, cell polarity, and differentiation. Besides, growing evidence indicates that extracellular matrix signaling, cell surface proteoglycans, and angiogenesis can contribute to cancer development. Given the genetic instability and vast intra-tumoral heterogeneity revealed by the single-cell sequencing of tumoral cells, the current approaches cannot eliminate the mutating cancer cells. Besides, the polyclonal expansion of tumor-infiltrated lymphocytes in response to tumoral neoantigens cannot elicit anti-tumoral immune responses due to the immunosuppressive tumor microenvironment. Nevertheless, the data from the single-cell sequencing of immune cells can provide valuable insights regarding the expression of inhibitory immune checkpoints/related signaling factors in immune cells, which can be used to select immune checkpoint inhibitors and adjust their dosage. Indeed, the integration of the data obtained from the single-cell sequencing of immune cells with immune checkpoint inhibitors can increase the response rate of immune checkpoint inhibitors, decrease the immune-related adverse events, and facilitate tumoral cell elimination. This study aims to review key pathways involved in tumor development and shed light on single-cell sequencing. It also intends to address the shortcomings of immune checkpoint inhibitors, i.e., their varied response rates among cancer patients and increased risk of autoimmunity development, via applying the data from the single-cell sequencing of immune cells.

scholarly journals P02.10 FocuSCOPE: a single cell, multi-omics solution to simultaneously analyze tumor variants and microenvironment

2021 ◽  
Vol 9 (Suppl 1) ◽  
pp. A12.1-A12
Author(s):  
Y Arjmand Abbassi ◽  
N Fang ◽  
W Zhu ◽  
Y Zhou ◽  
Y Chen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Tumor Microenvironment ◽  
Single Cell ◽  
High Throughput ◽  
Immune Cells ◽  
Genetic Variants ◽  
Expression Profiles ◽  
Single Cells ◽  
Gene Expression Profiles ◽  
Single Cell Sequencing

Recent advances of high-throughput single cell sequencing technologies have greatly improved our understanding of the complex biological systems. Heterogeneous samples such as tumor tissues commonly harbor cancer cell-specific genetic variants and gene expression profiles, both of which have been shown to be related to the mechanisms of disease development, progression, and responses to treatment. Furthermore, stromal and immune cells within tumor microenvironment interact with cancer cells to play important roles in tumor responses to systematic therapy such as immunotherapy or cell therapy. However, most current high-throughput single cell sequencing methods detect only gene expression levels or epigenetics events such as chromatin conformation. The information on important genetic variants including mutation or fusion is not captured. To better understand the mechanisms of tumor responses to systematic therapy, it is essential to decipher the connection between genotype and gene expression patterns of both tumor cells and cells in the tumor microenvironment. We developed FocuSCOPE, a high-throughput multi-omics sequencing solution that can detect both genetic variants and transcriptome from same single cells. FocuSCOPE has been used to successfully perform single cell analysis of both gene expression profiles and point mutations, fusion genes, or intracellular viral sequences from thousands of cells simultaneously, delivering comprehensive insights of tumor and immune cells in tumor microenvironment at single cell resolution.Disclosure InformationY. Arjmand Abbassi: None. N. Fang: None. W. Zhu: None. Y. Zhou: None. Y. Chen: None. U. Deutsch: None.

scholarly journals Applications of Single-Cell Omics to Dissect Tumor Microenvironment

2020 ◽  
Vol 11 ◽  
Author(s):  
Tingting Guo ◽  
Weimin Li ◽  
Xuyu Cai
Keyword(s):  
Tumor Microenvironment ◽  
Single Cell ◽  
Immune Cells ◽  
Immune Cell ◽  
Cell Types ◽  
Immune Checkpoint Blockade ◽  
Lineage Tracing ◽  
Great Success ◽  
Novel Technologies ◽  
Single Cell Sequencing

The recent technical and computational advances in single-cell sequencing technologies have significantly broaden our toolkit to study tumor microenvironment (TME) directly from human specimens. The TME is the complex and dynamic ecosystem composed of multiple cell types, including tumor cells, immune cells, stromal cells, endothelial cells, and other non-cellular components such as the extracellular matrix and secreted signaling molecules. The great success on immune checkpoint blockade therapy has highlighted the importance of TME on anti-tumor immunity and has made it a prime target for further immunotherapy strategies. Applications of single-cell transcriptomics on studying TME has yielded unprecedented resolution of the cellular and molecular complexity of the TME, accelerating our understanding of the heterogeneity, plasticity, and complex cross-interaction between different cell types within the TME. In this review, we discuss the recent advances by single-cell sequencing on understanding the diversity of TME and its functional impact on tumor progression and immunotherapy response driven by single-cell sequencing. We primarily focus on the major immune cell types infiltrated in the human TME, including T cells, dendritic cells, and macrophages. We further discuss the limitations of the existing methodologies and the prospects on future studies utilizing single-cell multi-omics technologies. Since immune cells undergo continuous activation and differentiation within the TME in response to various environmental cues, we highlight the importance of integrating multimodal datasets to enable retrospective lineage tracing and epigenetic profiling of the tumor infiltrating immune cells. These novel technologies enable better characterization of the developmental lineages and differentiation states that are critical for the understanding of the underlying mechanisms driving the functional diversity of immune cells within the TME. We envision that with the continued accumulation of single-cell omics datasets, single-cell sequencing will become an indispensable aspect of the immune-oncology experimental toolkit. It will continue to drive the scientific innovations in precision immunotherapy and will be ultimately adopted by routine clinical practice in the foreseeable future.

scholarly journals Deciphering the Prognostic Implications of the Components and Signatures in the Immune Microenvironment of Pancreatic Ductal Adenocarcinoma

2021 ◽  
Vol 12 ◽  
Author(s):  
Rong Tang ◽  
Xiaomeng Liu ◽  
Chen Liang ◽  
Jie Hua ◽  
Jin Xu ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Single Cell ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Cd8 T Cells ◽  
Nkt Cells ◽  
Ductal Adenocarcinoma ◽  
Hematopoietic Stem ◽  
Single Cell Sequencing ◽  
Prognostic Implications

Background: The treatment modalities for pancreatic ductal adenocarcinoma (PDAC) are limited and unsatisfactory. Although many novel drugs targeting the tumor microenvironment, such as immune checkpoint inhibitors, have shown promising efficacy for some tumors, few of them significantly prolong the survival of patients with PDAC due to insufficient knowledge on the tumor microenvironment.Methods: A single-cell RNA sequencing (scRNA-seq) dataset and seven PDAC cohorts with complete clinical and bulk sequencing data were collected for bioinformatics analysis. The relative proportions of each cell type were estimated using the gene set variation analysis (GSVA) algorithm based on the signatures identified by scRNA-seq or previous literature.Results: A meta-analysis of 883 PDAC patients showed that neutrophils are associated with worse overall survival (OS) for PDAC, while CD8+ T cells, CD4+ T cells, and B cells are related to prolonged OS for PDAC, with marginal statistical significance. Seventeen cell categories were identified by clustering analysis based on single-cell sequencing. Among them, CD8+ T cells and NKT cells were universally exhausted by expressing exhaustion-associated molecular markers. Interestingly, signatures of CD8+ T cells and NKT cells predicted prolonged OS for PDAC only in the presence of “targets” for pyroptosis and ferroptosis induction. Moreover, a specific state of T cells with overexpression of ribosome-related proteins was associated with a good prognosis. In addition, the hematopoietic stem cell (HSC)-like signature predicted prolonged OS in PDAC. Weighted gene co-expression network analysis identified 5 hub genes whose downregulation may mediate the observed survival benefits of the HSC-like signature. Moreover, trajectory analysis revealed that myeloid cells evolutionarily consisted of 7 states, and antigen-presenting molecules and complement-associated genes were lost along the pseudotime flow. Consensus clustering based on the differentially expressed genes between two states harboring the longest pseudotime span identified two PDAC groups with prognostic differences, and more infiltrated immune cells and activated immune signatures may account for the survival benefits.Conclusion: This study systematically investigated the prognostic implications of the components of the PDAC tumor microenvironment by integrating single-cell sequencing and bulk sequencing, and future studies are expected to develop novel targeted agents for PDAC treatment.

scholarly journals The Inflammatory Microenvironment in Hepatocellular Carcinoma: A Pivotal Role for Tumor-Associated Macrophages

2013 ◽  
Vol 2013 ◽  
pp. 1-15 ◽  
Author(s):  
Daria Capece ◽  
Mariafausta Fischietti ◽  
Daniela Verzella ◽  
Agata Gaggiano ◽  
Germana Cicciarelli ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Growth Factors ◽  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Signaling Pathways ◽  
Matrix Metalloproteases ◽  
Pivotal Role ◽  
M2 Macrophage ◽  
Tumor Associated Macrophages

Hepatocellular carcinoma (HCC) is one of the most common and aggressive human cancers worldwide. HCC is an example of inflammation-related cancer and represents a paradigm of the relation occurring between tumor microenvironment and tumor development. Tumor-associated macrophages (TAMs) are a major component of leukocyte infiltrate of tumors and play a pivotal role in tumor progression of inflammation-related cancer, including HCC. Several studies indicate that, in the tumor microenvironment, TAMs acquire an M2-polarized phenotype and promote angiogenesis, metastasis, and suppression of adaptive immunity through the expression of cytokines, chemokines, growth factors, and matrix metalloproteases. Indeed, an established M2 macrophage population has been associated with poor prognosis in HCC. The molecular links that connect cancer cells and TAMs are not completely known, but recent studies have demonstrated that NF-κB, STAT-3, and HIF-1 signaling pathways play key roles in this crosstalk. In this paper, we discuss the current knowledge about the role of TAMs in HCC development, highlighting the role of TAM-derived cytokines, chemokines, and growth factors in the initiation and progression of liver cancer and outlining the signaling pathways involved in the interplay between cancer cells and TAMs.

scholarly journals A Systematic Review on the Therapeutic Potentiality of PD-L1-Inhibiting MicroRNAs for Triple-Negative Breast Cancer: Toward Single-Cell Sequencing-Guided Biomimetic Delivery

Genes ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 1206
Author(s):  
Mahdi Abdoli Shadbad ◽  
Sahar Safaei ◽  
Oronzo Brunetti ◽  
Afshin Derakhshani ◽  
Parisa Lotfinejad ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Single Cell ◽  
Immune Checkpoint ◽  
Triple Negative ◽  
De Novo ◽  
Checkpoint Inhibitors ◽  
Oncogenic Signaling ◽  
Single Cell Sequencing ◽  
Oncogenic Signaling Pathways ◽  
Tumoral Cells

The programmed death-ligand 1 (PD-L1)/programmed cell death protein 1 (PD-1) is a well-established inhibitory immune checkpoint axis in triple-negative breast cancer (TNBC). Growing evidence indicates that tumoral PD-L1 can lead to TNBC development. Although conventional immune checkpoint inhibitors have improved TNBC patients’ prognosis, their effect is mainly focused on improving anti-tumoral immune responses without substantially regulating oncogenic signaling pathways in tumoral cells. Moreover, the conventional immune checkpoint inhibitors cannot impede the de novo expression of oncoproteins, like PD-L1, in tumoral cells. Accumulating evidence has indicated that the restoration of specific microRNAs (miRs) can downregulate tumoral PD-L1 and inhibit TNBC development. Since miRs can target multiple mRNAs, miR-based gene therapy can be an appealing approach to inhibit the de novo expression of oncoproteins, like PD-L1, restore anti-tumoral immune responses, and regulate various intracellular singling pathways in TNBC. Therefore, we conducted the current systematic review based on the preferred reporting items for systematic reviews and meta-analyses (PRISMA) to provide a comprehensive and unbiased synthesis of currently available evidence regarding the effect of PD-L1-inhibiting miRs restoration on TNBC development and tumor microenvironment. For this purpose, we systematically searched the Cochrane Library, Embase, Scopus, PubMed, ProQuest, Web of Science, Ovid, and IranDoc databases to obtain the relevant peer-reviewed studies published before 25 May 2021. Based on the current evidence, the restoration of miR-424-5p, miR-138-5p, miR-570-3p, miR-200c-3p, miR-383-5p, miR-34a-5p, miR-3609, miR-195-5p, and miR-497-5p can inhibit tumoral PD-L1 expression, transform immunosuppressive tumor microenvironment into the pro-inflammatory tumor microenvironment, inhibit tumor proliferation, suppress tumor migration, enhance chemosensitivity of tumoral cells, stimulate tumor apoptosis, arrest cell cycle, repress the clonogenicity of tumoral cells, and regulate various oncogenic signaling pathways in TNBC cells. Concerning the biocompatibility of biomimetic carriers and the valuable insights provided by the single-cell sequencing technologies, single-cell sequencing-guided biomimetic delivery of these PD-L1-inhibiting miRs can decrease the toxicity of traditional approaches, increase the specificity of miR-delivery, enhance the efficacy of miR delivery, and provide the affected patients with personalized cancer therapy.

scholarly journals RobustClone: A robust PCA method of tumor clone and evolution inference from single-cell sequencing data

2019 ◽  
Author(s):  
Ziwei Chen ◽  
Fuzhou Gong ◽  
Liang Ma ◽  
Lin Wan
Keyword(s):  
Single Cell ◽  
Large Scale ◽  
Principal Component ◽  
Low Rank ◽  
Breast Cancer Dataset ◽  
Sequencing Data ◽  
Cancer Dataset ◽  
Large Reservoir ◽  
Single Cell Sequencing ◽  
Model Free

AbstractSingle-cell sequencing (SCS) data provide unprecedented insights into intratumoral heterogeneity. With SCS, we can better characterize clonal genotypes and build phylogenetic relationships of tumor cells/clones. However, high technical errors bring much noise into the genetic data, thus limiting the application of evolutionary tools in the large reservoir. To recover the low-dimensional subspace of tumor subpopulations from error-prone SCS data in the presence of corrupted and/or missing elements, we developed an efficient computational framework, termed RobustClone, to recover the true genotypes of subclones based on the low-rank matrix factorization method of extended robust principal component analysis (RPCA) and reconstruct the subclonal evolutionary tree. RobustClone is a model-free method, fast and scalable to large-scale datasets. We conducted a set of systematic evaluations on simulated datasets and demonstrated that RobustClone outperforms state-of-the-art methods, both in accuracy and efficiency. We further validated RobustClone on 2 single-cell SNV and 2 single-cell CNV datasets and demonstrated that RobustClone could recover genotype matrix and infer the subclonal evolution tree accurately under various scenarios. In particular, RobustClone revealed the spatial progression patterns of subclonal evolution on the large-scale 10X Genomics scCNV breast cancer dataset. RobustClone software is available at https://github.com/ucasdp/RobustClone.

scholarly journals IMMU-01. SINGLE CELL SEQUENCING OF MELANOMA BRAIN METASTASES UNVEILS HETEROGENEITY OF THE TUMOR MICROENVIRONMENT IN RESPONSE TO IMMUNE CHECKPOINT BLOCKADE

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii104-ii104
Author(s):  
Christopher Alvarez-Breckenridge ◽  
Samuel Markson ◽  
Jackson Stocking ◽  
Matt Lastrapes ◽  
Naema Nayyar ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Brain Metastases ◽  
Single Cell ◽  
Immune Checkpoint ◽  
Heterogeneous Distribution ◽  
Single Cell Sequencing ◽  
Melanoma Brain Metastases ◽  
The Brain

Abstract Immune checkpoint inhibitors (ICI) have revolutionized oncologic treatment for metastatic melanoma. With improved systemic control, there has been increasing prevalence of patients with brain metastases. Recent evidence has demonstrated intracranial responses in a subset of these patients treated with ICI. We hypothesize that the response to ICI in melanoma brain metastases (MBM) is reflective of unique features within the tumor microenvironment of the brain. A cohort of 27 patients, encompassing 8 pre- and 19 post-immunotherapy MBM underwent single cell RNA sequencing (Smart-Seq2). The cohort includes patients with longitudinal cranial resections and simultaneously resected, spatially distinct tumors. Each tumor underwent unsupervised transcriptomic analysis, differential gene expression, inferred copy number variation, and T-cell receptor (TCR) clonotyping. Published extracranial melanoma single cell datasets were used to compare the tumor microenvironment of the brain and periphery in response to ICI. A total of 14,027 cells (6,189 malignant, 7,838 non-malignant) were sequenced. Brain metastases demonstrated a heterogeneous distribution of macrophage states. Intracranial macrophages were found to be more tumor-supportive than their extracranial counterparts. MBM also included a distribution of reactive neutrophils and astrocytes. Analysis across pre- and post-treatment MBM demonstrated an increase in clonally expanded T cells in patients responding to ICI. Across longitudinal brain metastases collected from the same patients, there was evidence of identical T cell clones across timepoints and locations. Single cell sequencing of MBM provides insights into the cellular composition of the tumor and microenvironment. Our data suggest the cellular heterogeneity within MBM is unique when compared to extracranial disease. Additionally, T cell clonal expansion is found following ICI and T cells of the same clonotype infiltrate spatially and temporally separated brain metastases. These findings raise potential therapeutic implications as we learn to target the differential features of the innate and adaptive immune system within brain metastases and their extracranial counterparts.

scholarly journals A single-cell atlas of hepatocellular carcinoma.

2019 ◽  
Vol 5 (suppl) ◽  
pp. 46-46
Author(s):  
Ankur Sharma
Keyword(s):  
Hepatocellular Carcinoma ◽  
Endothelial Cells ◽  
Tumor Microenvironment ◽  
Liver Cancer ◽  
Single Cell ◽  
Stromal Cells ◽  
Tumor Heterogeneity ◽  
Rna Seq ◽  
Therapeutic Targeting ◽  
Complex Ecosystem

46 Background: Tumors reside and evolve in a complex ecosystem of immune and non-immune stromal cells. Methods: We employed multi-sectoral single-cell RNA-seq to catalogue intra-tumor heterogeneity in human hepatocellular carcinoma (HCC). Results: We generated single-cell atlas of ~76,000 cells from fourteen HCC patients, each consisting of 2-5 tumor and matched adjacent normal sectors. In total, we profiled 57 individual tumor and normal sectors consisting of HBV+ and HBV- HCC. By analysing matched normal and malignant sectors we observed intriguing remodelling of the tumor microenvironment (TME).We identify >70 distinct cells-states in HCC including novel, previously uncharacterized subpopulations. Specifically, we demonstrate remarkable heterogeneity in hepatocytes, fibroblast and endothelial cells. Most importantly, we consistently observed a marked remodellingof stromal cells suggesting a role in dynamic tumor-TME interactions. Conclusions: We present the first comprehensive single-cell atlas of HCC. This resource provides unprecedented insights into liver cancer, which will pave the way for early detection and therapeutic targeting.

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