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

Abstract

PurposeTumor-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.MethodsWe 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).ResultsA 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).ConclusionsTAMs could serve as independent predictive indicators and therapeutic targets for HCC. Further trials are needed to elucidate the exact relationship and the underlying mechanism.

Infiltration of T Cells and Programmed Cell Death Ligand 1-expressing Macrophages as a Potential Predictor of Lenvatinib Response in Hepatocellular Carcinoma

“…25 In general, TAMs exhibit the M2 phenotype, and their infiltration is known to be associated with poor prognosis in HCC. 9,11,26 However, the…”

“…1,9 Moreover, the infiltration of various immune cells, such as tumor-associated macrophages (TAMs), leads to an immunosuppressive microenvironment. 10,11 However, only 14-18% of the patients who receive pembrolizumab or nivolumab monotherapy demonstrate objective tumor responses. [12][13][14] Moreover, unlike that in other solid tumors, no significant association was identified between tumor cell programmed cell death ligand 1 (PD-L1) expression and anti-PD-1 responses in HCC, as reported by the Keynote-224 and CheckMate-040 studies.…”

Prognostic significance of tumor-associated macrophages in patients with nasopharyngeal carcinoma

“…[ 25 ] CD68 is the most extensively used marker of macrophages and is used to identify overall TAMs. [ 26 , 27 ] Whereas M1 and M2 subsets of TAMs are identified according to polarization. [ 28 ] M1 TAMs are known to induce inflammation and play a crucial role in anti-tumor activity.…”

“…In the present meta-analysis, the results showed the prognostic of CD68+ TAMs in IT was also not significant for OS in patients with NPC, which was in accordance with the results of SCCHN. [ 34 ] Referring relevant meta-analyses on TAMs, [ 10 , 27 , 35 , 36 ] I defined TAMs as CD68+ as the overall cell population and CD163+, CD68+CCL18+, and CD206+ as M2-like TAMs. The tissue distribution (IT and/or TS) was used to further stratify the location of diverse subsets of TAMs.…”

Immune System Efficiency in Cancer and the Microbiota Influence

“…As discussed in the previous section, the differentiation of TAMs in the TME can contribute for their pro-tumor characteristics [42, 85]. In this regard, several meta-analysis have clearly demonstrated that an increase in the number of TAMs is generally associated with poor prognosis [86, 87]. During cancer progression, several mechanisms have been identified to overcome antitumor response by TAMs including the secretion of prostaglandin E2 [88], the immunosuppressive cytokine IL-10 [89], the angiogenic factors such as IL-1β, that through upregulation of HIF-1α protein increases vascular endothelial growth factor (VEGF) secretion [90], VEGF [91], endothelin-2 [92], and epidermal growth factor family ligands [93].…”