Meta-Analysis of the Prognostic and Clinical Value of Tumor-Associated Macrophages in Hepatocellular Carcinoma

Abstract

Background: Tumor-associated macrophages (TAMs) are key components of the cancer microenvironment. This meta-analysis aimed to determine the association between TAMs and hepatocellular carcinoma (HCC). Methods: All studies investigating macrophages in HCC from January 2008 to May 2018 were retrieved by searching the Cochrane Library, EMBASE, PubMed, Chinese National Knowledge Infrastructure, and Wanfang databases. The associations of TAMs with overall survival (OS), disease-free survival (DFS) and the corresponding hazard ratios (HRs) or odds ratios (ORs) with 95% confidence intervals (CIs) were pooled for analysis. Heterogeneity was assessed by using the Q test and I² statistic. Statistical analyses were performed with Stata 13.0. Results: Seventeen articles with a total of 3547 patients were included in this meta-analysis. The pooled analysis showed that a high density of M2 TAMs in intratumor (IT) was significantly correlated with OS (HR = 1.58, 95%CI = 1.15–2.00), and the subgroup analysis suggested the significant difference in CD206⁺M2 TAMs (HR = 1.74, 95%CI = 1.26–2.21). However, the high expression levels of CD68⁺M1 TAMs in the IT or peritumor (PT) were not related with OS (CD68 in IT:HR = 1.30, 95%CI = 0.88–1.72;CD68 in PT:HR = 1.39, 95%CI = 0.93–1.85). Furthermore, a high density of CD206⁺M2 TAMs in IT showed a significant association with vascular invasion (OR = 2.18, 95%CI = 1.38–3.44) and more advanced TNM stage (OR = 2.38, 95%CI = 1.12–5.07). Conclusions: CD68⁺M1 TAMs have no prognostic effects on OS.A high density of M2 TAMs in IT is associated with poor prognosis in HCC, and CD206⁺ M2 TAMs can be used as a prognostic biomarker in HCC. However, the limit sample sizes might cause potential publication bias, thus more trails on CD206 are needed.

Keywords:

• Tumor-associated macrophages
• hepatocellular carcinoma
• prognostic significance
• clinical value
• immune response

Additional information

Funding

This work was supported by the National Natural Science Foundation of China #1 under Grant 81874436; and a Science Research Project of the Thirteen Five-year Plan #2 under Grant 2018ZX10725504; and the three-year action plan to further accelerate the development of traditional Chinese medicine in Shanghai #3 under Grant ZY (2018-2020)-CCCX-2003-01; and the Municipal Hospital’s Emerging Cutting-edge Technology joint Research Project #4 under Grant SHDC12016121; and the Shanghai Science and Technology Commission support project #5 under Grant 16401970600; and the Chinese medicine preponderant disease breeding project #6 under Grant zybz-2017004.