Type I IFNs repolarized a CD169+ macrophage population with anti-tumor potentials in hepatocellular carcinoma.

Macrophages constitute a major component in human hepatocellular carcinoma (HCC) and perform various functions to facilitate disease progression. Reprogramming or reconstituting the tumor surveillance phenotypes of macrophages represents an attractive immunotherapeutic strategy in cancer treatments. The current study identified CD169 as a potential target for macrophage repolarization since it signified a population of macrophages positively correlated with an activated immune signature and better prognosis of patients with HCC. In vitro experiments revealed that a low dose of type I interferon (IFN) could effectively reprogram human monocyte-derived macrophages to upregulate CD169 expression, and such induced CD169+ macrophages exhibited significantly enhanced phagocytotic and CD8+ T cell-activating capacities compared to controls. A low dose of IFNα also inhibited hepatoma growth in mice in vivo, presumably through polarizing the CD169+ macrophage population and enhancing CD8+ T cell activities. Notably, IFNα also induced substantial PD-L1 expression on macrophages in vivo, and thus blockade of PD-L1 could further increase the anti-tumor efficacy of IFNα in the treatment of HCC. We propose a low dose of IFNα in combination with a PD-L1 blocking agent as a potential anti-tumor therapeutic strategy via its effects on macrophage polarization.

High S100A9+ cell density predicts a poor prognosis in hepatocellular carcinoma patients after curative resection.

S100A9 is differentially expressed in various cell types and is associated with the development, progression and metastasis of various cancers. However, the expression, distribution, and clinical significance of S100A9 in hepatocellular carcinoma (HCC) remain unclear. In the present study, The Cancer Genome Atlas (TCGA) database was used to examine S100A9 gene expression in HCC; we found that S100A9 expression was associated with HCC prognosis. In addition, S100A9 protein expression was assessed by immunohistochemistry analysis of tissues from 382 HCC patients. We found that the infiltration of S100A9+ cells in both tumor and nontumor tissues could predict poor overall survival (P = 0.0329, tumor; P = 0.0003, nontumor) and a high recurrence risk (P = 0.0387, tumor; P = 0.0015, nontumor) in our tissue microarray analysis. Furthermore, immunofluorescence double staining revealed that the primary S100A9-expressing cells in adjacent nontumoral tissue were CD15+ neutrophils, and both CD68+ macrophages and CD15+ neutrophils expressed S100A9 in HCC tumor tissues. Taken together, the results suggest that high S100A9+ cell density predicts a poor prognosis in HCC patients, and S100A9 expression could potentially serve as an independent prognostic marker for HCC.

Targeting adenosinergic pathway enhances the anti-tumor efficacy of sorafenib in hepatocellular carcinoma.

BACKGROUND: Sorafenib is the most widely used first-line treatment for patients with advanced hepatocellular carcinoma (HCC), but such treatment provides only limited survival benefits that might be related to the immune status of distinct tumor microenvironments. A fundamental understanding of the distribution and phenotypes of T lymphocytes in tumors will undoubtedly lead to the development of novel immunotherapeutic strategies that could possibly enhance the efficacy of sorafenib treatments. METHODS: Flow cytometry, immunohistochemistry and immunofluorescence analyses were performed to detect the infiltration and distribution of various leukocyte populations, and the expression of different immune checkpoint molecules in fresh HCC tumor tissues. Correlations among indicating genes were calculated in 365 patients with HCC from The Cancer Genome Atlas (TCGA) data set, and the cumulative overall survival time was calculated using the Kaplan-Meier method. Moreover, role of adenosinergic pathway on sorafenib anti-tumor efficacy was investigated using both subcutaneous and orthotopic transplantation tumor model in immune competent C57BL/6 mice. RESULTS: We revealed that levels of CD3+ and CD8+ T cells were significantly downregulated in HCC tumor tissue, so were the infiltration of CD169+ cells (a Mφ subpopulation with T cell activation capacities) and their contact with CD8+ cells in tumor milieus. Moreover, levels of PD-1 and CD39 expression were significantly upregulated in human HCC-infiltrating CD4+ and CD8+ T cells, and CD39+CD8+ T cells exhibited a CD69+PD-1+perforinlowIFNγlow "exhausted" phenotype. Levels of both CD39+ T cells infiltration and adenosine receptor ADORA2B expression in tumor tissues were negatively correlated with overall survival of patients with HCC. Accordingly, mice treated with sorafenib in combination with adenosine A2B receptor blockage reagents exhibited significantly reduced tumor progression compared with control groups. CONCLUSIONS: These results suggest that adenosinergic pathway might represent an applicable target for sorafenib-combined-therapies in human HCC.

[Clinical study of the effect of verapamil-procaine compound in prevention and treatment of acute respiratory distress syndrome after high risk operation].

OBJECTIVE: To observe the effect of verapamil-procaine compound (V-P) on prevention and treatment of acute respiratory distress syndrome (ARDS) subsequent to high risk operation. METHODS: Altogether 150 cases of major operations with high risk of ARDS were enrolled for study. They were randomly divided into three groups. V-P group: 5% glucose 500 ml and procaine 1 250 mg and verapamil 10 mg; procaine group: 5% glucose 500 ml and procaine 1 250 mg; control group: only glucose was given. The injection speed of the three groups were the same, and it was kept at 0.5 ml x h(-1) x kg(-1). The dosages of verapamil and procaine in V-P group and procaine group were doubled when the diagnosis of acute lung injury (ALI) or ARDS was confirmed. UT4000F was used in monitoring (non-invasive) blood pressure (BP), electrocardiogram (ECG), pulse oxygen saturation (SpO(2)), respiratory rate, and temperature. Blood routine and arterial blood gases measurements were intermittently performed. Diagnosis of systemic inflammatory response syndrome (SIRS), ALI and ARDS was made respectively according to published diagnostic criteria. SIRS score and acute physiology and chronic health evaluation II (APACHEII) score were performed. RESULTS: Eleven cases in V-P group, 26 in procaine group, and 42 in control group manifested symptoms and signs of SIRS. There were notable differences among groups (all P<0.01). Four patients in V-P group, 7 in procaine group, and 19 in control group were shown to develop ALI. Significant difference was found between control and V-P or procaine group (both P<0.01), but no significant difference was found between procaine group and V-P group. Twelve cases were complicated with ARDS in control group 2 weeks after the operation, and among them 5 died of multiple organ failure. There was significant difference between control group and V-P group or procaine group (both P<0.01). Two patients were complicated with acute renal failure in V-P group, 2 in procaine group, and 5 in control group. CONCLUSION: The V-P can interrupt SIRS to develop ALI, then ARDS and multiple organ dysfunction syndrome(MODS), and thus prevents and cures ARDS.