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

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.

研究目的：肿瘤相关巨噬细胞（Tumor-associated macrophages，TAMs）在实体瘤中具有临床病理及预后调控作用，因而受到广泛关注。然而，TAMs在肝细胞癌（hepatocellular carcinoma，HCC）患者中的预后价值仍存在争议。本研究通过荟萃分析旨在解决这一争议。
研究方法：本研究从Cochrane图书馆、Embase及PubMed数据库中检索相关研究。根据纳入研究的异质性，采用固定效应模型或随机效应模型计算风险比（hazard ratios，HRs）与95%置信区间（confidence intervals，CIs）。此外，本研究还开展了亚组分析、累积荟萃分析、敏感性分析以及偏倚分析（Egger检验）。
研究结果：本研究共纳入20项观察性研究，涉及4297例患者。针对TAMs亚群，瘤内区域（intratumor，IT）或瘤周区域（peritumor，PT）内高浸润密度的CD68+ TAMs均与不良总生存期（Overall Survival，OS）相关（合并风险比=1.417；95%置信区间=1.092~1.839；P=0.009；合并风险比=1.393；95%置信区间=1.022~1.899；P=0.036）。瘤内区域高浸润密度的CD68+ TAMs还与甲胎蛋白（Alpha-fetoprotein，AFP）水平升高、肿瘤体积增大、无包膜、存在血管侵犯以及较晚的肿瘤-淋巴结-转移（tumor-nodes-metastasis，TNM）分期显著相关。血清中高浸润密度的CD163+巨噬细胞与不良总生存期相关（合并风险比=5.698；95%置信区间=3.062~10.603；P<0.001）。瘤内区域高浸润密度的CD204+ TAMs与不良总生存期相关（合并风险比=1.947；95%置信区间=1.387~2.733；P<0.001）。瘤内区域高浸润密度的CD206+ TAMs与不良总生存期（合并风险比=1.723；95%置信区间=1.308~2.270；P<0.001）及无病生存期（Disease-Free Survival，DFS）均相关（合并风险比=1.711；95%置信区间=1.214~2.412；P=0.002）。然而，瘤内区域高浸润密度的CD169+ TAMs与良好总生存期相关（合并风险比=0.471；95%置信区间=0.343~0.647；P=0.037）。
研究结论：TAMs可作为肝细胞癌患者的独立预后预测指标及治疗靶点。未来仍需开展更多研究以阐明二者间的确切关联及潜在分子机制。