Current perspectives on the immunosuppressive tumor microenvironment in hepatocellular carcinoma: challenges and opportunities

Chen, Lu; Ding, Rong; Zhang, Betty; Wen-ling, Zheng; Wang, Xuehao; Chen, Ziyi; Tang, Weiwei

doi:10.1186/s12943-019-1047-6

Cited by 329 publications

(271 citation statements)

References 129 publications

(114 reference statements)

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“…An existing study reported that neutrophil infiltration within HCC might display an association with a poor clinical outcome [36]. Neutrophils contribute to the activation, regulation and effector function of immune cells [37]; they are also capable of HCC progression by secreting a wide range of cytokines [38], thereby demonstrating their crucial role in the pathogenesis of HCC. A number of studies have reported that increased macrophages were related to poor prognosis in HCC [39].…”

Section: Discussionmentioning

confidence: 99%

Development and validation of a novel immune-related prognostic model in hepatocellular carcinoma

et al. 2020

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Background: Growing evidence has suggested that immune-related genes play crucial roles in the development and progression of hepatocellular carcinoma (HCC). Nevertheless, the utility of immune-related genes for evaluating the prognosis of HCC patients are still lacking. The study aimed to explore gene signatures and prognostic values of immune-related genes in HCC. Methods:We comprehensively integrated gene expression data acquired from 374 HCC and 50 normal tissues in The Cancer Genome Atlas (TCGA). Differentially expressed genes (DEGs) analysis and univariate Cox regression analysis were performed to identify DEGs that related to overall survival. An immune prognostic model was constructed using the Lasso and multivariate Cox regression analyses. Furthermore, Cox regression analysis was applied to identify independent prognostic factors in HCC. The correlation analysis between immune-related signature and immune cells infiltration were also investigated. Finally, the signature was validated in an external independent dataset.Results: A total of 329 differentially expressed immune-related genes were detected. 64 immune-related genes were identified to be markedly related to overall survival in HCC patients using univariate Cox regression analysis. Then we established a TF-mediated network for exploring the regulatory mechanisms of these genes. Lasso and multivariate Cox regression analyses were applied to construct the immune-based prognostic model, which consisted of nine immune-related genes. Further analysis indicated that this immune-related prognostic model could be an independent prognostic indicator after adjusting to other clinical factors. The relationships between the risk score model and immune cell infiltration suggested that the nine-gene signature could reflect the status of tumor immune microenvironment. The prognostic value of this nine-gene prognostic model was further successfully validated in an independent database.Conclusions: Together, our study screened potential prognostic immune-related genes and established a novel immune-based prognostic model of HCC, which not only provides new potential prognostic biomarkers and therapeutic targets, but also deepens our understanding of tumor immune microenvironment status and lays a theoretical foundation for immunotherapy.

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Section: Discussionmentioning

confidence: 99%

Development and validation of a novel immune-related prognostic model in hepatocellular carcinoma

et al. 2020

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“…Although adoptive transfer of TCR‐T cells has shown significant clinical response in solid tumors, such as melanoma and synovial cell sarcoma, the success of TCR‐T therapy for HCC is still challenging. The strong immune suppressive microenvironment of HCC, characterized by the presence of immunosuppressive cells and elevated expression of immune checkpoint molecules, poses a major barrier to clinical efficacy in immunotherapy. Therefore, TCR‐T therapy in combination with methods for modulating the tumor microenvironment, such as checkpoint blockage, may represent a favorable strategy for HCC immunotherapy.…”

Section: Discussionmentioning

confidence: 99%

Identification of an HLA‐A*24:02‐restricted α‐fetoprotein signal peptide‐derived antigen and its specific T‐cell receptor for T‐cell immunotherapy

Gong²,

Liu³

et al. 2020

Immunology

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Summary Hepatocellular carcinoma (HCC) is the most common type of liver cancer with limited treatments. Asia has the highest HCC incidence rates; China accounts for over 50% of all HCC cases worldwide. T‐cell receptor (TCR) ‐engineered T‐cell immunotherapies specific for human leukocyte antigen (HLA) ‐A*02:01‐restricted α‐fetoprotein (AFP) peptide have shown encouraging results in clinics. HLA‐A*24:02 is more common than HLA‐A*02:01 in Asian countries, including China. Here we identified a novel HLA‐A*24:02‐restricted peptide KWVESIFLIF (AFP2–11) located in AFP signal peptide domain by mass spectrometric analysis of HLA‐bound peptides from HepG2 cells. A TCR (KWV3.1) specific for AFP2–11‐HLA‐A*24:02 was isolated from peripheral blood mononuclear cells of a healthy donor. The binding affinity of soluble KWV3.1 to its antigen was determined to be ~55 μm, within the affinity range of native TCRs for self‐antigens. KWV3.1‐transfected T cells could specifically activate and kill AFP2–11 pulsed T2‐A24 cells and AFP+ HLA‐A*24:02+ tumor cell lines, demonstrating that AFP2–11 can be naturally presented on the surface of AFP+ tumor cell lines. The newly identified antigenic peptide can provide a novel target for immunotherapeutic strategies for patients with AFP+ HLA‐A*24:02+ HCC.

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“…We determined none of our observations changed substantially 13 (Supplemental Data), demonstrating that the observed differences are mediated through other 14 age-related factors. Thus, we conclude the T cell infiltration decreases, macrophage infiltration 15 increases, and NK infiltration stability despite an increasing abundance in the body overall is 16 most likely attributable to the hypothesis that exhausted or senescent phenotypes develop in 17 immune cells as individuals age and make the immune cells of older patients more sensitive to 18 the immunosuppressive signaling that is produced by most tumors (Lu et al, 2019). Another 19 possibility is that some other aspect of aging biology extrinsic to immune cells interacts with the 20 dysregulated signaling from tumors to prevent immune infiltration of certain cell types.…”

mentioning

confidence: 89%

Aging interacts with tumor biology to produce major changes in the immune tumor microenvironment

Erbe

Wang

Zaidi

et al. 2020

Preprint

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1Advanced age is strongly correlated with both increased cancer incidence and general immune 2 decline. The immune tumor microenvironment (ITME) has been established as an important 3 prognostic of both therapeutic efficacy and overall patient survival. Thus, age-related immune 4 decline is an important consideration for the treatment of a large subset of cancer patients. 5Current studies of aging-related immune alterations are predominantly performed on non-6 cancerous tissue, requiring additional study into the effects of age on tumor immune infiltration. 7We leverage large scale transcriptional data sets from The Cancer Genome Atlas and the 8 Genotype-Tissue Expression project to distinguish normal age-related immune alterations from 9 age-related changes in tumor immune infiltration. We demonstrate that while there is overlap 10 between the normal immune aging phenotype and that of the ITME, there are several changes 11 in immune cell abundance that are specific to the ITME, particularly in T cell, NK cell, and 12Macrophage populations. These results suggest that aged immune cells are more susceptible to 13 tumor suppression of cytotoxic immune cell infiltration and activity than normal tissues, which 14 creates an unfavorable ITME in older patients in excess of normal immune decline with age and 15 may inform the application of existing and emerging immunotherapies for this large population 16 of patients. We additionally identify that age-related increases in tumor mutational burden are 17 associated with decreased DNA methylation and increased expression of the immune 18 checkpoint genes PDL1, CD80, and LAG3 which may have implications for therapeutic 19 application of immune checkpoint blockade in older patients. 20 21

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Current perspectives on the immunosuppressive tumor microenvironment in hepatocellular carcinoma: challenges and opportunities

Cited by 329 publications

References 129 publications

Development and validation of a novel immune-related prognostic model in hepatocellular carcinoma

Development and validation of a novel immune-related prognostic model in hepatocellular carcinoma

Identification of an HLA‐A*24:02‐restricted α‐fetoprotein signal peptide‐derived antigen and its specific T‐cell receptor for T‐cell immunotherapy

Aging interacts with tumor biology to produce major changes in the immune tumor microenvironment

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