scholarly journals The Identification and Validation of Two Heterogenous Subtypes and a Risk Signature Based on Ferroptosis in Hepatocellular Carcinoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Zaoqu Liu ◽  
Libo Wang ◽  
Long Liu ◽  
Taoyuan Lu ◽  
Dechao Jiao ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Chromatin Remodeling ◽  
Vascular Invasion ◽  
Immune Escape ◽  
Immune Checkpoints ◽  
Related Risk ◽  
Tumorigenesis And Progression ◽  
Immunosuppressive Cells ◽  
Immune Escape Mechanisms ◽  
Worse Prognosis

BackgroundFerroptosis is essential for tumorigenesis and progression of hepatocellular carcinoma (HCC). The heterogeneity of ferroptosis and its relationship with tumor microenvironment (TME) have still remain elusive.MethodsBased on 74 ferroptosis related genes (FRGs) and 3,933 HCC samples from 32 datasets, we comprehensively explored the heterogenous ferroptosis subtypes. The clinical significance, functional status, immune infiltration, immune escape mechanisms, and genomic alterations of different subtypes were further investigated.ResultsWe identified and validated two heterogeneous ferroptosis subtypes: C1 was metabolismlowimmunityhigh subtype and C2 was metabolismhighimmunitylow subtype. Compared to C2, C1 owned worse prognosis, and C1 tended to occur in the patients with clinical characteristics such as younger, female, advanced stage, higher grade, vascular invasion. C1 and C2 were more sensitive to immunotherapy and sorafenib, respectively. The immune escape mechanisms of C1 might be accumulating more immunosuppressive cells, inhibitory cytokines, and immune checkpoints, while C2 was mainly associated with inferior immunogenicity, defecting in antigen presentation, and lacking leukocytes. In addition, C1 was characterized by BAP1 mutation, MYC amplification, and SCD1 methylation, while C2 was characterized by the significant alterations in cell cycle and chromatin remodeling processes. We also constructed and validated a robust and promising signature termed ferroptosis related risk score (FRRS) for assessing prognosis and immunotherapy.ConclusionWe identified and validated two heterogeneous ferroptosis subtypes and a reliable risk signature which used to assess prognosis and immunotherapy. Our results facilitated the understood of ferroptosis as well as clinical management and precise therapy of HCC.

scholarly journals Comprehensive Molecular Analyses of a Novel Mutational Signature Classification System with Regard to Prognosis, Genomic Alterations, and Immune Landscape in Glioma

2021 ◽  
Vol 8 ◽  
Author(s):  
Zaoqu Liu ◽  
Taoyuan Lu ◽  
Libo Wang ◽  
Long Liu ◽  
Lifeng Li ◽  
...  
Keyword(s):  
Immune Escape ◽  
Molecular Classification ◽  
Idh1 Mutation ◽  
Immune Checkpoints ◽  
Chromosome 1P ◽  
Molecular Features ◽  
Public Datasets ◽  
Carcinogenic Process ◽  
Immunosuppressive Cells ◽  
Immune Escape Mechanisms

Background: Glioma is the most common malignant brain tumor with complex carcinogenic process and poor prognosis. The current molecular classification cannot fully elucidate the molecular diversity of glioma.Methods: Using broad public datasets, we performed cluster analysis based on the mutational signatures and further investigated the multidimensional heterogeneity of the novel glioma molecular subtypes. The clinical significance and immune landscape of four clusters also investigated. The nomogram was developed using the mutational clusters and clinical characteristics.Results: Four heterogenous clusters were identified, termed C1, C2, C3, and C4, respectively. These clusters presented distinct molecular features: C1 was characterized by signature 1, PTEN mutation, chromosome seven amplification and chromosome 10 deletion; C2 was characterized by signature 8 and FLG mutation; C3 was characterized by signature 3 and 13, ATRX and TP53 mutations, and 11p15.1, 11p15.5, and 13q14.2 deletions; and C4 was characterized by signature 16, IDH1 mutation and chromosome 1p and 19q deletions. These clusters also varied in biological functions and immune status. We underlined the potential immune escape mechanisms: abundant stromal and immunosuppressive cells infiltration and immune checkpoints (ICPs) blockade in C1; lack of immune cells, low immunogenicity and antigen presentation defect in C2 and C4; and ICPs blockade in C3. Moreover, C4 possessed a better prognosis, and C1 and C3 were more likely to benefit from immunotherapy. A nomogram with excellent performance was also developed for assessing the prognosis of patients with glioma.Conclusion: Our results can enhance the mastery of molecular features and facilitate the precise treatment and clinical management of glioma.

scholarly journals A novel immune classification reveals distinct immune escape mechanism and genomic alterations: implications for immunotherapy in hepatocellular carcinoma

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Zaoqu Liu ◽  
Yuyuan Zhang ◽  
Chengcheng Shi ◽  
Xueliang Zhou ◽  
Kaihao Xu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Immune Cell ◽  
Immune Escape ◽  
Pi3k Pathway ◽  
Single Patient ◽  
Genomic Alterations ◽  
Time Index ◽  
Immunosuppressive Cells ◽  
Immune Escape Mechanisms ◽  
Geo Database

Abstract Background The tumor immunological microenvironment (TIME) has a prominent impact on prognosis and immunotherapy. However, the heterogeneous TIME and the mechanisms by which TIME affects immunotherapy have not been elucidated in hepatocellular carcinoma (HCC). Methods A total of 2195 eligible HCC patients from TCGA and GEO database were collected. We comprehensively explored the different heterogeneous TIME phenotypes and its clinical significance. The potential immune escape mechanisms and what genomic alterations may drive the formation of different phenotypes were further investigated. Results We identified three phenotypes in HCC: TIME-1, the “immune-deficiency” phenotype, with immune cell depletion and proliferation; TIME-2, the “immune-suppressed” phenotype, with enrichment of immunosuppressive cells; TIME-3, the “immune-activated phenotype”, with abundant leukocytes infiltration and immune activation. The prognosis and sensitivity to both sorafenib and immunotherapy differed among the three phenotypes. We also underlined the potential immune escape mechanisms: lack of leukocytes and defective tumor antigen presentation capacity in TIME-1, increased immunosuppressive cells in TIME-2, and rich in immunoinhibitory molecules in TIME-3. The different phenotypes also demonstrated specific genomic events: TIME-1 characterized by TP53, CDKN2A, CTNNB1, AXIN1 and FOXD4 alterations; TIME-2 characterized by significant alteration patterns in the PI3K pathway; TIME-3 characterized by ARID1A mutation. Besides, the TIME index (TI) was proposed to quantify TIME infiltration pattern, and it was a superior prognostic and immunotherapy predictor. A pipeline was developed to classify single patient into one of these three subtypes and calculated the TI. Conclusions We identified three TIME phenotypes with different clinical outcomes, immune escape mechanisms and genomic alterations in HCC, which could present strategies for improving the efficacy of immunotherapy. TI as a novel prognostic and immunotherapeutic signature that could guide personalized immunotherapy and clinical management of HCC.

scholarly journals A Novel Immune Classification Reveals Distinct Immune Escape Mechanism and Genomic Alterations: Implications for Immunotherapy in Hepatocellular Carcinoma

2020 ◽  
Author(s):  
Zaoqu Liu ◽  
Yuyuan Zhang ◽  
Chengcheng Shi ◽  
Xueliang Zhou ◽  
Kaihao Xu ◽  
...  
Keyword(s):  
Immune Deficiency ◽  
Hepatocellular Carcinoma ◽  
Immune Cell ◽  
Immune Escape ◽  
Pi3k Pathway ◽  
Genomic Alterations ◽  
Time Index ◽  
Immunosuppressive Cells ◽  
Immune Escape Mechanisms ◽  
Geo Database

Abstract BackgroundThe tumor immunological microenvironment (TIME) has a prominent impact on prognosis and immunotherapy. However, the heterogeneous TIME and the mechanisms by which TIME affects immunotherapy have not been elucidated in hepatocellular carcinoma (HCC).MethodsA total of 2195 eligible HCC patients from TCGA and GEO database were collected. We comprehensively explored the different heterogeneous TIME phenotypes and its clinical significance. The potential immune escape mechanisms and what genomic alterations may drive the formation of different phenotypes were further investigated.ResultsWe identified three phenotypes in HCC: TIME-1, the “immune-deficiency” phenotype, with immune cell depletion and proliferation; TIME-2, the “immune-suppressed” phenotype, with being in immunosuppressive states; TIME-3, the “immune-activated phenotype”, with abundant leukocytes infiltration and immune activation. The prognosis and sensitivity to both sorafenib and immunotherapy differed among the three phenotypes. We also underlined the potential immune escape mechanisms: lack of leukocytes and defective tumor antigen presentation capacity in TIME-1, increased immunosuppressive cells in TIME-2, and rich in immunoinhibitory molecules in TIME-3. The different phenotypes also demonstrated specific genomic events: TIME-1 characterized by TP53, CDKN2A, CTNNB1, AXIN1 and FOXD4 alterations; TIME-2 characterized by significant alteration patterns in the PI3K pathway; TIME-3 characterized by ARID1A mutation. Besides, the TIME index (TI) was proposed to quantify TIME infiltration pattern, and it was a superior prognostic and immunotherapy predictor. ConclusionsWe identified three TIME phenotypes with different clinical outcomes, immune escape mechanisms and genomic alterations in HCC, which could present strategies for improving the efficacy of immunotherapy. TI as a novel prognostic and immunotherapeutic signature that could guide personalized immunotherapy and clinical management of HCC.

scholarly journals A Novel Immune Classification Reveals Distinct Immune Escape Mechanism and Genomic Alterations: Implications for Immunotherapy in Hepatocellular Carcinoma

2020 ◽  
Author(s):  
Zaoqu Liu ◽  
Yuyuan Zhang ◽  
Chengcheng Shi ◽  
Xueliang Zhou ◽  
Kaihao Xu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Immune Cell ◽  
Immune Escape ◽  
Pi3k Pathway ◽  
Single Patient ◽  
Genomic Alterations ◽  
Time Index ◽  
Immunosuppressive Cells ◽  
Immune Escape Mechanisms ◽  
Geo Database

Abstract Background: The tumor immunological microenvironment (TIME) has a prominent impact on prognosis and immunotherapy. However, the heterogeneous TIME and the mechanisms by which TIME affects immunotherapy have not been elucidated in hepatocellular carcinoma (HCC).Methods: A total of 2195 eligible HCC patients from TCGA and GEO database were collected. We comprehensively explored the different heterogeneous TIME phenotypes and its clinical significance. The potential immune escape mechanisms and what genomic alterations may drive the formation of different phenotypes were further investigated.Results: We identified three phenotypes in HCC: TIME-1, the “immune-deficiency” phenotype, with immune cell depletion and proliferation; TIME-2, the “immune-suppressed” phenotype, with being in immunosuppressive states; TIME-3, the “immune-activated phenotype”, with abundant leukocytes infiltration and immune activation. The prognosis and sensitivity to both sorafenib and immunotherapy differed among the three phenotypes. We also underlined the potential immune escape mechanisms: lack of leukocytes and defective tumor antigen presentation capacity in TIME-1, increased immunosuppressive cells in TIME-2, and rich in immunoinhibitory molecules in TIME-3. The different phenotypes also demonstrated specific genomic events: TIME-1 characterized by TP53, CDKN2A, CTNNB1, AXIN1 and FOXD4 alterations; TIME-2 characterized by significant alteration patterns in the PI3K pathway; TIME-3 characterized by ARID1A mutation. Besides, the TIME index (TI) was proposed to quantify TIME infiltration pattern, and it was a superior prognostic and immunotherapy predictor. A pipeline was developed to classify single patient into one of these three subtypes and calculated the TI. Conclusions: We identified three TIME phenotypes with different clinical outcomes, immune escape mechanisms and genomic alterations in HCC, which could present strategies for improving the efficacy of immunotherapy. TI as a novel prognostic and immunotherapeutic signature that could guide personalized immunotherapy and clinical management of HCC.

scholarly journals Multi-omics Analysis of Microenvironment Characteristics and Immune Escape Mechanisms of Hepatocellular Carcinoma

2019 ◽  
Vol 9 ◽  
Author(s):  
Wenli Li ◽  
Huimei Wang ◽  
Zhanzhong Ma ◽  
Jian Zhang ◽  
Wen Ou-yang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Immune Escape ◽  
Omics Analysis ◽  
Immune Escape Mechanisms

scholarly journals Immune Escape Mechanisms in Non Small Cell Lung Cancer

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3605
Author(s):  
Andrea Anichini ◽  
Valentina E. Perotti ◽  
Francesco Sgambelluri ◽  
Roberta Mortarini
Keyword(s):  
Lung Cancer ◽  
Immune Evasion ◽  
Immune Escape ◽  
Early Stage ◽  
Human Leukocyte ◽  
Immune Checkpoint Blockade ◽  
Immune Checkpoints ◽  
Normal Lung ◽  
Early Stage Nsclc ◽  
Immune Escape Mechanisms

Development of strong immune evasion has been traditionally associated with the late stages of solid tumor progression, since advanced cancers are more likely to have reached the third phase of the immunoediting process. However, by integrating a variety of approaches, evidence for active immune escape mechanisms has been found even in the pre-invasive lesions that later progress to the main NSCLC histotypes. Pre-invasive lesions of adenocarcinoma (LUAD) and of squamous cell carcinoma (LUSC) can show impaired antigen presentation, loss of heterozygosity at the Human Leukocyte Antigen (HLA) region, neoantigen silencing, activation of immune checkpoints, altered TH1/TH2 cytokine ratios, and immune contexture evolution. Analysis of large panels of LUAD vs. LUSC, of early stage NSCLC vs. normal lung tissue, of specific molecular subsets of NSCLC, and of distinct regions within the same tumor, indicates that all these processes of immune escape continue to evolve in the invasive stage of NSCLC, are associated with inter- and intra-tumor heterogeneity, and contribute to resistance to therapy by immune checkpoint blockade (ICB). In this review, we will discuss the most recent evidence on immune escape mechanisms developing from the precursor to invasive stage in NSCLC, and the contribution of immune evasion to resistance to ICB in lung cancer.

scholarly journals Immune Checkpoint Inhibition in Classical Hodgkin Lymphoma: From Early Achievements towards New Perspectives

2019 ◽  
Vol 2019 ◽  
pp. 1-16 ◽  
Author(s):  
Diego De Goycoechea ◽  
Gregoire Stalder ◽  
Filipe Martins ◽  
Michel A. Duchosal
Keyword(s):  
Hodgkin Lymphoma ◽  
Immune Checkpoint ◽  
Immune Escape ◽  
Response Rates ◽  
Genetic Alterations ◽  
Immune Checkpoints ◽  
Checkpoint Inhibition ◽  
Immune Checkpoint Inhibition ◽  
Classical Hodgkin Lymphoma ◽  
Immune Escape Mechanisms

Immune checkpoint inhibition (ICI) became one of the major breakthroughs in cancer treatment over the past decade and entered into therapy within standard oncohematology practice. ICI has demonstrated impressive response rates as salvage therapy in relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL) and is now being tested as an adjunction to chemotherapy in the frontline settings. CHL exquisite sensitivity to PD-1/PD-L1 axis inhibition relies on a particular biological background. By contrast, non-Hodgkin lymphomas (NHL) have demonstrated heterogeneous response rates using ICI. These observations highlight discrepancies between various types of lymphomas in terms of genetic alterations, immune microenvironment interactions, and disease phenotype. This review aims to focus on cHL immune escape mechanisms, focusing on cHL biological sensitivity to PD-1 blockade. We will summarize the available data issued from clinical trials on ICI in cHL and its safety profile. Going beyond the current use of monoclonal antibodies (mAb) targeting immune checkpoints in clinical practice, we will offer an overview of new combinatory therapeutic perspectives where cHL immunotherapy may be considered.

PD1/PD-L1 Axis in Uro-oncology

2020 ◽  
Vol 21 (13) ◽  
pp. 1293-1300 ◽  
Author(s):  
Kerstin Junker ◽  
Markus Eckstein ◽  
Michelangelo Fiorentino ◽  
Rodolfo Montironi
Keyword(s):  
Tumor Cells ◽  
Standard Treatment ◽  
Immune Escape ◽  
Current Knowledge ◽  
Tumor Development ◽  
Immune Checkpoints ◽  
Urological Malignancies ◽  
Immune Therapies ◽  
Control Tumor ◽  
Immune Escape Mechanisms

The immune system is important to control tumor development and progression in humans. However, tumor cells and cells of the tumor microenvironment can induce immune escape mechanisms including activation of immune checkpoints such as PD-1/PD-L1. Based on this knowledge, new immune therapies, including PD-1 and PD-L1 inhibition, have been developed and are already recommended as a standard treatment in metastatic bladder and kidney cancer patients. In addition to its role as a therapeutic target, PD-L1 seems to be a prognostic parameter although data are controversial. Only little is known about signaling pathways inducing PD-L1 expression in tumor cells on one hand and about its functional role for tumor cells itself. However, the understanding of the complex biological function of PD-L1 will improve therapeutic options in urological malignancies. This review is giving an overview of the current knowledge concerning the PD-1/PD-L1 axis in urological tumors including bladder, kidney, prostate, testicular and penile cancer.

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