Clinical significance of infiltration of M2 tumor-associated macrophage in hepatocellular carcinoma / 中华消化杂志

ABSTRACT

Objective:To investigate the distribution of M2 tumor-associated macrophage (TAM) in hepatocellular carcinoma (HCC) and their correlation with clinicopathological features, and the significance of programmed death-ligand 1 (PD-L1) expression.Methods:From January 1, 2012 to December 31, 2020, a total of 320 HCC patients who underwent surgical resection at the Third People′s Hospital of Nantong were included. The distribution of CD163 labeled and PD-L1 CD163 double-labeled M2 TAM in HCC tissues was detected by immunohistochemistry, and the cell density was calculated. The cell density> the average cell density (112/mm 2) was judged as high-density, the cell density≤ the average cell density was judged as low-density. The correlation between CD163 positive and PD-L1 CD163 double positive M2 TAM density and the clinical pathological characteristics of HCC and its impact on prognosis were analyzed. Chi-square test was used to analyze the correlation between M2 TAM expression and the clinical pathological characteristics of HCC. Kaplan-Meier method was used to draw survival curves, and log-rank test was used for inter group comparison. Univariate and multivariate Cox proportional hazards regression analysis was used to indentify the relevant factors affecting the prognosis of HCC. Results:TAM were mainly distributed in the tumor edge stroma and tumor sinusoids, CD163 positive M2 TAM were the main macrophage subtype. PD-L1 expression was observed in CD163 positive M2 TAM in HCC tissues, and PD-L1 positive M2 TAM were mainly distributed in the tumor edge stroma. The rate of high-density CD163 positive M2 TAM in HCC tissues was 44.4% (142/320). High-density CD163 positive M2 TAM was correlated with histological grade, TNM stage, and PD-L1 expression on tumor infiltrating immune cells in HCC tissues ( χ2=4.65, 6.72 and 42.19, P=0.031, =0.011 and <0.001). High-density PD-L1 and CD163 double positive M2 TAM in HCC tissues was correlated with microvascular invasion and TNM stage ( χ2=11.96 and 8.74, P=0.001 and 0.004). The median disease-free survival (DFS) time and overall survival (OS) time of patients with high-density CD163 positive M2 TAM were 21 and 36 months, respectively, which were lower than those of patients with low-density CD163 positive M2 TAM (50 and 103 months, respectively); the median DFS time and OS time of patients with high-density PD-L1 CD163 double-positive M2 TAM were 12 and 15 months, respectively, which were lower than those of patients with low-density PD-L1 CD163 double-positive M2 TAM (28 and 45 months, respectively), and the differences were statistically significant (all log-rank tests, all P<0.001). The results of multivariate Cox proportional hazards regression analysis showed that high-density CD163 positive M2 TAM, microvascular invasion and high TNM stage were independent risk factors for evaluating DFS and OS of patients with HCC (DFS time HR=2.408 (95% confidence interval (95% CI) 1.778 to 3.261), 2.603 (95% CI 1.860 to 3.641), 4.032 (95% CI 2.833 to 5.747), all P<0.001. OS time HR=2.007 (95% CI 1.457 to 2.764), 4.144 (95% CI 2.881 to 5.960), 4.292 (95% CI 2.915 to 6.329), all P<0.001). Conclusions:High-density of CD163 positive M2 TAM in HCC tissues indicates high malignancy and poor prognosis, and it is an independent prognostic risk factor. The expression of PD-L1 in M2 TAM suggests stronger tumor aggressiveness and worse prognosis in HCC.