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 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 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 Integrative Transcriptomic, Proteomic and Functional Analysis Reveals ATP1B3 as a Diagnostic and Potential Therapeutic Target in Hepatocellular Carcinoma

2021 ◽  
Vol 12 ◽  
Author(s):  
Shanshan Lu ◽  
Shenglan Cai ◽  
Xiaozhen Peng ◽  
Ruochan Cheng ◽  
Yiya Zhang
Keyword(s):  
Hepatocellular Carcinoma ◽  
Functional Analysis ◽  
Prognostic Factor ◽  
Epithelial To Mesenchymal Transition ◽  
Immune Cell ◽  
Prognostic Significance ◽  
Independent Prognostic Factor ◽  
Mesenchymal Transition ◽  
Immune Infiltration ◽  
Geo Database

The Na+/K+-ATPase (NKA), has been proposed as a signal transducer involving various pathobiological processes, including tumorigenesis. However, the clinical relevance of NKA in hepatocellular carcinoma (HCC) has not been well studied. This study revealed the upregulation of mRNA of ATP1A1, ATP1B1, and ATP1B3 in HCC using TCGA, ICGC, and GEO database. Subsequently, ATP1B3 was demonstrated as an independent prognostic factor of overall survival (OS) of HCC. To investigate the potential mechanisms of ATP1B3 in HCC, we analyzed the co-expression network using LinkedOmics and found that ATP1B3 co-expressed genes were associated with immune-related biological processes. Furthermore, we found that ATP1B3 was correlated immune cell infiltration and immune-related cytokines expression in HCC. The protein level of ATP1B3 was also validated as a prognostic significance and was correlated with immune infiltration in HCC using two proteomics datasets. Finally, functional analysis revealed that ATP1B3 was increased in HCC cells and tissues, silenced ATP1B3 repressed HCC cell proliferation, migration, and promoted HCC cell apoptosis and epithelial to mesenchymal transition (EMT). In conclusion, these findings proved that ATP1B3 could be an oncogene and it was demonstrated as an independent prognostic factor and correlated with immune infiltration in HCC, revealing new insights into the prognostic role and potential immune regulation of ATP1B3 in HCC progression and provide a novel possible therapeutic strategy for 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 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 Cross-platform meta-analysis reveals common matrisome variation associated with tumor genotypes and immunophenotypes in human cancers

2018 ◽  
Author(s):  
Su Bin Lim ◽  
Swee Jin Tan ◽  
Wan-Teck Lim ◽  
Chwee Teck Lim
Keyword(s):  
Immune Cell ◽  
Immune Escape ◽  
Wide Spectrum ◽  
Meta Analysis ◽  
Immune Checkpoints ◽  
Tumor Immune Escape ◽  
Data Resource ◽  
Specific Tumor ◽  
Cross Platform ◽  
Immune Escape Mechanisms

AbstractBackgroundRecent sequencing efforts unveil genomic landscapes of the tumor microenvironment. Yet, little is known about the extent to which matrisome pattern is conserved in progressive tumors across diverse cancer types, and thus its clinical impact remains largely unexplored.FindingsUsing a newly generated, unified data resource, we conducted cross-platform assessment of a measure of altered extra-cellular matrix (ECM) composition and remodeling associated with tumor progression, termed as the matrisome index (TMI). Parallel analyses with TCGA in over 30,000 patient-derived biopsies revealed that TMI is closely associated with mutational load, tumor histopathology, and predictive of patient outcomes. We found an enrichment of specific tumor-infiltrating immune cell populations, signatures predictive of immunotherapy resistance, and several immune checkpoints in tumors with high TMI, suggesting potential role of ECM interaction with immunophenotyes and tumor immune escape mechanisms. Both epithelial cancer cells and carcinoma-associated fibroblasts are potential cellular contributors of such deregulated matrisome.ConclusionsDespite wide spectrum of genetic heterogeneity and dynamic nature, matrisome abnormalities are integral to disease progression. Our resource of a curated compendium of 8,386 genome-wide profiles, molecular and clinical associations, and matrisome-tumor genotype-immunophenotype relationships identify potentially actionable immune targets that may guide personalized immunotherapy.

scholarly journals Immune Escape Mechanisms and Their Clinical Relevance in Head and Neck Squamous Cell Carcinoma

2020 ◽  
Vol 21 (19) ◽  
pp. 7032
Author(s):  
Barbara Seliger ◽  
Chiara Massa ◽  
Bo Yang ◽  
Daniel Bethmann ◽  
Matthias Kappler ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Tumor Microenvironment ◽  
Cell Carcinoma ◽  
Head And Neck ◽  
Squamous Cell ◽  
Immune Cell ◽  
Immune Escape ◽  
Neck Squamous Cell Carcinoma ◽  
Physical Factors ◽  
Immune Escape Mechanisms

Immunotherapy has been recently approved for the treatment of relapsed and metastatic human papilloma virus (HPV) positive and negative head and neck squamous cell carcinoma (HNSCC). However, the response of patients is limited and the overall survival remains short with a low rate of long-term survivors. There exists growing evidence that complex and partially redundant immune escape mechanisms play an important role for the low efficacy of immunotherapies in this disease. These are caused by diverse complex processes characterized by (i) changes in the expression of immune modulatory molecules in tumor cells, (ii) alterations in the frequency, composition and clonal expansion of immune cell subpopulations in the tumor microenvironment and peripheral blood leading to reduced innate and adaptive immune responses, (iii) impaired homing of immune cells to the tumor site as well as (iv) the presence of immune suppressive soluble and physical factors in the tumor microenvironment. We here summarize the major immune escape strategies of HNSCC lesions, highlight pathways, and molecular targets that help to attenuate HNSCC-induced immune tolerance, affect the selection and success of immunotherapeutic approaches to overcome resistance to immunotherapy by targeting immune escape mechanisms and thus improve the HNSCC patients’ outcome.

scholarly journals P03.15 Site-specific immune evasion and substantial heterogeneity within entities provide evidence for personalized immunotherapy

2020 ◽  
Vol 8 (Suppl 2) ◽  
pp. A28-A29
Author(s):  
M Thelen ◽  
K Wennhold ◽  
J Lehmann ◽  
E Staib ◽  
MA Garcia Marquez ◽  
...  
Keyword(s):  
T Cells ◽  
Antigen Presentation ◽  
Immune Evasion ◽  
Immune Cell ◽  
Immune Escape ◽  
Immune Cell Infiltration ◽  
Site Specific ◽  
Immune Escape Mechanisms ◽  
Substantial Heterogeneity ◽  
Research Grant

BackgroundImmune-checkpoint inhibition (CKI) demonstrated remarkable therapeutic efficacy in several kinds of cancer. However, immune escape mechanisms lead to primary or secondary resistance in the majority of patients. Most predictive biomarkers failed, as the primary target of CKI is not the tumor cell itself, but the crosstalk between immune- and cancer cells. We aimed to characterize the immune evasion landscape in primary tumors across different entities.Materials and MethodsExpression of 32 immune-regulatory molecules on lymphocytes was analyzed in peripheral blood and tumor infiltrating lymphocytes (TILs) of 146 primary tumor patients across 10 different entities using flow cytometry. NanoString was applied to determine RNA expression of the respective ligands and 20 genes associated with antigen presentation. Expression of coinhibitory ligands on tumor cells was assessed by immunohistochemistry. To quantify the immune cell infiltration, digital pathology was used and the Immunoscore was generated for each patient.ResultsWhile an increase of regulatory T cells was a common feature across all entities, we found site-specific differences regarding other lymphocyte subsets and expression of immune-regulatory molecules by TILs and tumor cells. Expression of co-inhibitory molecules on tumor infiltrating T cells accumulated especially in advanced stage cancers whereas immune cell infiltration was mainly associated with enhanced antigen presentation. Co-expression of multiple immune-inhibitory ligands was most frequent in colorectal, lung and ovarian carcinoma. Genes related to antigen presentation were frequently dysregulated in seminoma, liver and lung cancer.ConclusionsImmune evasion is a common feature of cancer and frequently detected co-occurrence of multiple mechanisms probably contributes to resistance against immunotherapy. We describe substantial heterogeneity regarding immune escape mechanisms between patients with the same primary tumor. Individualized immunotherapeutic strategies based on pretherapeutic evaluation of the immune evasion landscape might help to improve response to CKI.Disclosure InformationM. Thelen: None. K. Wennhold: None. J. Lehmann: None. E. Staib: None. M.A. Garcia Marquez: None. P. Lohneis: None. A. Lechner: None. S. Wagener-Ryczek: None. P.S. Plum: None. D. Pfister: None. F. Dörr: None. D. Beutner: None. F. Thangarajah: None. D. Ratiu: None. W. Malter: None. S. Merkelbach-Bruse: None. C.J. Bruns: None. A. Quaas: None. M.S. von Bergwelt-Baildon: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Significant; Astellas. F. Consultant/Advisory Board; Modest; Bristol-Myers Squibb. H.A. Schlößer: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Significant; Astra Zeneca.

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