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Clinicopathologic and prognostic significance of tumor-associated macrophages in patients with hepatocellular carcinoma: A meta-analysis.

ABSTRACT: PURPOSE:Tumor-associated macrophages (TAMs) deserve more focus because of its clinicopathologic and prognostic roles in solid tumors. However, the prognostic value of TAMs in patients with hepatocellular carcinoma (HCC) is still controversial. We performed a meta-analysis to resolve the issue. METHODS:We selected relevant studies from the Cochrane Library, Embase and PubMed databases. The hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated employing fixed-effect or random-effect models depending on the heterogeneity of the included trials. Moreover, we also performed subgroup analysis, cumulative meta-analysis, sensitivity analysis, and bias analysis (Egger's test). RESULTS:A total of 20 observational studies with 4297 patients were enrolled. For TAMs subsets, high density of CD68+ TAMs in either intratumor (IT) (pooled HR = 1.417; 95% CI = 1.092-1.839; P = 0.009) or peritumor (PT) (pooled HR = 1.393; 95% CI = 1.022-1.899; P = 0.036) was associated with a poor OS. High density of CD68+ TAMs in IT was also associated with high AFP value, large tumor size, absent encapsulation, present vascular invasion, and later tumor-nodes-metastasis (TNM) stage. High density of CD163+ macrophages in serum was associated with a poor OS (pooled HR = 5.698; 95% CI = 3.062-10.603; P < 0.001). High density of CD204+ TAMs in IT was associated with a poor OS (pooled HR = 1.947; 95% CI = 1.387-2.733; P < 0.001. High density of CD206+ TAMs in IT was associated with a poor OS (pooled HR = 1.723; 95% CI = 1.308-2.270; P < 0.001) and DFS (pooled HR = 1.711; 95% CI = 1.214-2.412; P = 0.002). However, high density of CD169+ TAMs in IT was associated with a good OS (pooled HR = 0.471; 95% CI = 0.343-0.647; P = 0.037). CONCLUSIONS:TAMs could serve as independent predictive indicators and therapeutic targets for HCC. Further trials are needed to elucidate the exact relationship and the underlying mechanism.

SUBMITTER: Ding W

PROVIDER: S-EPMC6795444 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Clinicopathologic and prognostic significance of tumor-associated macrophages in patients with hepatocellular carcinoma: A meta-analysis.

Ding Wei W Tan Yulin Y Qian Yan Y Xue Wenbo W Wang Yibo Y Jiang Peng P Xu Xuezhong X

PloS one 20191016 10

<h4>Purpose</h4>Tumor-associated macrophages (TAMs) deserve more focus because of its clinicopathologic and prognostic roles in solid tumors. However, the prognostic value of TAMs in patients with hepatocellular carcinoma (HCC) is still controversial. We performed a meta-analysis to resolve the issue.<h4>Methods</h4>We selected relevant studies from the Cochrane Library, Embase and PubMed databases. The hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated employing fixed-effect ...[more]

PMID: 31618252

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Project description:BackgroundHepatocellular carcinoma (HCC) is an inflammation-associated tumor involved in immune tolerance and evasion in the immune microenvironment. Immunotherapy can enhance the immune response of the body, break immune tolerance, and then recognize and kill tumor cells. The polarization homeostasis of M1 and M2 macrophages in tumor microenvironment (TME) is involved in the occurrence and development of tumors and has been considered a hot topic in tumor research. Programmed cell death ligand 1 (PD-L1) plays an important role in the polarity of TAM and affects the prognosis of HCC patients as a target of immunotherapy. To this end, efforts were hereby made to further explore the application value of PD-L1, M1 macrophages (CD86), and M2 macrophages (CD206) in the prognosis assessment of HCC, their correlation with immune cell infiltration in HCC tissues, and their bioenrichment function.MethodsThe gene expression omnibus (GEO) and the Cancer Genome Atlas (TCGA) database were used to analyze the expression of PD-L1, CD86, and CD206 in different tumor tissues. The correlation between the expression of PD-L1, CD86, and CD206 and the infiltration of immune cells was analyzed using the Tumor Immune Estimation Resource (TIMER). The tissue specimens and clinicopathological data of hepatocellular carcinoma patients having undergone surgical treatment in our hospital were collected. Immunohistochemistry was used to verify the expression of PD-L1, CD86, and CD206, and analyze the relationship with clinicopathological features and prognosis of patients. Besides, nomogram was constructed to predict the overall survival (OS) of patients at 3 and 5 years. Finally, the protein-protein interaction network information was analyzed using STRING database, and GO analysis and KEGG (Kyoto Encyclopedia of Genes and Genomes) analysis were performed to study the biological functions of PD-L1, CD86, and CD206.ResultBioinformatics analysis found that PD-L1, CD86, and CD206 were underexpressed in various tumor tissues including liver cancer, while the present immunohistochemical detection found that PD-L1, CD86, and CD206 were overexpressed in liver cancer tissues. Expressions of PD-L1, CD86, and CD206 were positively correlated with the infiltration level of immune cells in liver cancer, while the expression of PD-L1 was positively correlated with the degree of tumor differentiation. Meanwhile, the expression level of CD206 was positively correlated with gender and preoperative hepatitis, and patients with high expression of PD-L1 or low expression of CD86 had poor prognosis. AJCC stage, preoperative hepatitis, and the expression levels of PD-L1 and CD86 in cancer tissues were independent risk factors affecting survival of patients after radical hepatoma surgery. KEGG pathway enrichment analysis showed that PD-L1 was significantly enriched in T cell aggregation and lymphocyte aggregation, and might be involved in the formation of T cell antigen receptor CD3 complex and cell membrane. Besides, CD86 was significantly enriched in positive regulation of cell adhesion, regulation of mononuclear cell proliferation, regulation of leukocyte proliferation, and transduction of T cell receptor signaling pathway, while CD206 was significantly enriched in type 2 immune response, cellular response to LPS, cellular response to LPS, and involvement in cellular response to LPS.ConclusionIn conclusion, these results suggest that PD-L1, CD86, and CD206 may be involved not only in the occurrence and development of HCC, but also in immune regulation, indicating the potential role of PD-L1 and CD86 as potential biomarkers and new therapeutic targets for prognosis assessment of liver cancer.

Project description:BackgroundsHepatocellular Carcinoma (HCC) is one of the most common malignancy of liver and HCC-related morbidity and mortality remains at high level. Researchers had investigated whether and how reduced E-cadherin expression impacted the prognosis of patients with HCC but the results reported by different teams remain inconclusive.MethodsA systematic literature search was performed in all available databases to retrieve eligible studies and identify all relevant data, which could be used to evaluate the correlation between reduced E-cadherin expression and clinicopathological features and prognosis for HCC patients. A fixed or random effects model was used in this meta-analysis to calculate the pooled odds ratios (OR) and weighted mean differences (WMD) with 95% confidence intervals (CI).ResultsTotal 2439 patients in thirty studies matched the selection criteria. Aggregation of the data suggested that reduced E-cadherin expression in HCC patients correlated with poor 1-, 3- and 5-year overall survival. The combined ORs were 0.50 (n = 13 studies, 95% CI: 0.37-0.67, Z = 4.49, P<0.00001), 0.39 (n = 13 studies, 95% CI: 0.28-0.56, Z = 5.12, P<0.00001), 0.40 (n = 11 studies, 95% CI: 0.25-0.64, Z = 3.82, P = 0.0001), respectively. Additionally, the pooled analysis denoted that reduced E-cadherin expression negatively impacts recurrence-free survival (RSF) with no significant heterogeneity. The pooled ORs for 1-, 3- and 5- year RSF affected by down-regulated E-cadherin were 0.73 (n = 6 studies, 95% CI: 0.54-1.00, Z = 1.95, P = 0.05), 0.70 (n = 6 studies, 95% CI: 0.52-0.95, Z = 2.32, P = 0.02), 0.66 (n = 5 studies, 95% CI: 0.48-0.90, Z = 2.64, P = 0.008). And what's more, reduced E-cadherin expression tended to be significantly associated with metastasis (OR = 0.31, 95% CI: 0.16-0.60, Z = 3.50, P = 0.0005), vascular invasion (OR = 0.76, 95% CI: 0.59-0.98, Z = 2.14, P = 0.03), advanced differentiation grade (OR = 0.31, 95% CI: 0.21-0.45, Z = 6.04, P<0.00001) and advanced TMN stage (T3/T4 versus T1/T2) (OR = 0.61,95% CI:0.38-0.98, Z = 2.05, P = 0.04).ConclusionsReduced E-cadherin expression indicates a poor prognosis for patients with HCC, and it may have predictive potential for prognosis of HCC patients.

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Clinicopathologic and prognostic significance of tumor-associated macrophages in patients with hepatocellular carcinoma: A meta-analysis.

Publications

Clinicopathologic and prognostic significance of tumor-associated macrophages in patients with hepatocellular carcinoma: A meta-analysis.

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