The predictive value of tumor infiltrating leukocytes in Hepatocellular Carcinoma: A systematic review and meta-analysis

Schoenberg, Markus Bo; Li, Xiaokang; Li, Xinyu; Han, Yantao; Hao, Jihua; Miksch, Rainer Christoph; Koch, Dominik; Börner, N.; Beger, Nicola; Bucher, Julian Nikolaus; Schiergens, Tobias S.; Guba, Markus; Werner, Jens; Bazhin, Alexandr V.

doi:10.1016/j.ejso.2021.04.042

Cited by 21 publications

(21 citation statements)

References 47 publications

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“…In addition, it is widely reported that FASLG and IL2RB were specifically expressed in T cells ( 47 – 50 ). High infiltration of T cells was associated with low recurrence rate in HCC ( 51 , 52 ), and cytotoxic T cells were key contributors to anticancer immunity in multiple cancers ( 53 – 55 ). Thus, positive correlation between the expressions of FASLG/IL2RB and T cell markers suggested that FASLG/IL2RB might promote T cell-induced anticancer immunity in HCC.…”

Section: Discussionmentioning

confidence: 99%

Integrative Analysis Identifies Cell-Type-Specific Genes Within Tumor Microenvironment as Prognostic Indicators in Hepatocellular Carcinoma

Huang

et al. 2022

Front. Oncol.

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BackgroundHepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, but effective early detection and prognostication methods are lacking. MethodsThe Cox regression model was built to stratify the HCC patients. The single-cell RNA sequencing data analysis and gene set enrichment analysis were employed to investigate the biological function of identified markers. PLCB1 gain- or loss-of-function experiments were performed, and obtained HCC samples were analyzed using quantitative real-time PCR and immunohistochemistry assay to validate the biological function of identified markers.ResultsIn this study, we developed a model using optimized markers for HCC recurrence prediction. Specifically, we screened out 8 genes through a series of data analyses, and built a multivariable Cox model based on their expression. The risk stratifications using the Eight-Gene Cox (EGC) model were closely associated with the recurrence-free survivals (RFS) in both training and three validation cohorts. We further demonstrated that this risk stratification could serve as an independent predictor in predicting HCC recurrence, and that the EGC model could outperform other models. Moreover, we also investigated the cell-type-specific expression patterns of the eight recurrence-related genes in tumor microenvironment using single-cell RNA sequencing data, and interpreted their functional roles from correlation and gene set enrichment analyses, in vitro and in vivo experiments. Particularly, PLCB1 and SLC22A7 were predominantly expressed in malignant cells, and they were predicted to promote angiogenesis and to help maintain normal metabolism in liver, respectively. In contrast, both FASLG and IL2RB were specifically expressed in T cells, and were highly correlated with T cell marker genes, suggesting that these two genes might assist in maintaining normal function of T cell-mediated immune response in tumor tissues.ConclusionIn conclusion, the EGC model and eight identified marker genes could not only facilitate the accurate prediction of HCC recurrence, but also improve our understanding of the mechanisms behind HCC recurrence.

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Section: Discussionmentioning

confidence: 99%

Integrative Analysis Identifies Cell-Type-Specific Genes Within Tumor Microenvironment as Prognostic Indicators in Hepatocellular Carcinoma

Huang

et al. 2022

Front. Oncol.

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“…This is inconsistent with the increase in Tregs caused by pTLS described earlier, and a clear association has been found between Tregs and the pathogenesis of HCC and even other cancers ( 57 , 81 , 82 ). Tregs play a strong immunosuppressive role and promote immune escape ( 83 , 84 ). The decrease in Tregs in the results suggest pTLS weakening on suppression of the tumor microenvironment (TME), which may be one of the reasons for the discrepancy between the findings by Li et al.…”

Section: Effect Of Tls On Phc Prognosismentioning

confidence: 99%

“…Therefore, it is speculated that the cellular components of TLS have a relatively direct impact on the prognosis of PHC, and our findings seem to confirm this. In TLS, patients with high CD3, CD8, and NK cell infiltration have a better prognosis ( 83 ). High levels of CD3 and CD8 infiltration in TILs have a better prognostic value for OS.…”

Section: Effect Of Tls On Phc Prognosismentioning

confidence: 99%

“…FOXP3 expression in natural T cells is helpful in obtaining effective immunosuppressive ability, and FOXP3 Tregs/CD4 T cell ratio is an independent prognostic factor for OS ( 99 , 100 ). Tregs promote immune escape in tumors, which inhibits the activity of T cells, bone marrow cells, and stromal cells, leading to T-cell dysfunction ( 83 , 84 ). WNT/β-catenin inhibitor ICG-001 plus radiotherapy (RT) can promote CD8+ T-cell infiltration and IFN-γ production in TILs and simultaneously reduce the number of Tregs, thus contributing to HCC treatment ( 101 , 102 ).…”

Section: Effect Of Tls On Phc Prognosismentioning

confidence: 99%

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Tertiary Lymphatic Structures in Primary Hepatic Carcinoma: Controversy Cannot Overshadow Hope

et al. 2022

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Tertiary lymphoid structures (TLSs) are organized aggregates of immune cells found in the tumor microenvironment. TLS can influence primary hepatic carcinoma (PHC) occurrence and have an active role in cancer. TLS can promote or inhibit the growth of PHC depending on their location, and although available findings are controversial, they suggest that TLS have a protective role in PHC tissues and a non-protective role in paracancerous tissues. In addition, the cellular composition of TLS can also influence the outcome of PHC. As an immunity marker, TLS can act as a marker of immunotherapy to predict its effect and help to identify patients who will respond well to immunotherapy. Modulation of TLS formation through the use of chemokines/cytokines, immunotherapy, or induction of high endothelial vein to interfere with tumor growth has been studied extensively in PHC and other cancers. In addition, new tools such as genetic interventions, cellular crosstalk, preoperative radiotherapy, and advances in materials science have been shown to influence the prognosis of malignant tumors by modulating TLS production. These can also be used to develop PHC treatment.

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“…A meta-analysis showed that a higher infiltration of CD3 T cells, CD8 T cells, and natural killer cells was associated with better overall survival (OS), disease-free survival (DFS), and recurrence-free survival (RFS). In contrast, a higher infiltration of Tregs and neutrophils indicated lower OS and DFS[ 35 ]. Another report also showed that an increase of Tregs or a decrease of M1 macrophages (proinflammatory phenotype) were associated with a poor prognosis of HCC patients[ 36 ].…”

Section: Tregs In Chronic Liver Diseasementioning

confidence: 99%

Regulatory T cells and their associated factors in hepatocellular carcinoma development and therapy

Zhang¹,

Liu²,

Yang³

2022

WJG

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Liver cancer is the third leading cause of cancer-related death worldwide with primary type hepatocellular carcinoma (HCC). Factors, including carcinogens, infection of hepatitis viruses, alcohol abuse, and non-alcoholic fatty liver disease (NAFLD), can induce HCC initiation and promote HCC progression. The prevalence of NAFLD accompanying the increased incidence of obesity and type 2 diabetes becomes the most increasing factor causing HCC worldwide. However, the benefit of current therapeutic options is still limited. Intrahepatic immunity plays critically important roles in HCC initiation, development, and progression. Regulatory T cells (Tregs) and their associated factors such as metabolites and secreting cytokines mediate the immune tolerance of the tumor microenvironment in HCC. Therefore, targeting Tregs and blocking their mediated factors may prevent HCC progression. This review summarizes the functions of Tregs in HCC-inducing factors including alcoholic and NAFLD, liver fibrosis, cirrhosis, and viral infections. Overall, a better understanding of the role of Tregs in the development and progression of HCC provides treatment strategies for liver cancer treatment.

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The predictive value of tumor infiltrating leukocytes in Hepatocellular Carcinoma: A systematic review and meta-analysis

Cited by 21 publications

References 47 publications

Integrative Analysis Identifies Cell-Type-Specific Genes Within Tumor Microenvironment as Prognostic Indicators in Hepatocellular Carcinoma

Integrative Analysis Identifies Cell-Type-Specific Genes Within Tumor Microenvironment as Prognostic Indicators in Hepatocellular Carcinoma

Tertiary Lymphatic Structures in Primary Hepatic Carcinoma: Controversy Cannot Overshadow Hope

Regulatory T cells and their associated factors in hepatocellular carcinoma development and therapy

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