Identification of a Macrophage marker gene signature to evaluate immune infiltration and therapeutic response in hepatocellular carcinoma.

Background: Only a minority of hepatocellular carcinoma (HCC) patients can benefit from systemic regimens. Macrophages, which abundantly infiltrate in HCC, could mediate tumour microenvironment remodelling and immune escape, proving to be powerful weapons in combating HCC. Thus, a deeper understanding of macrophages is necessary for improving existing antitumour treatments. Methods: With a series of bioinformatic approaches, we comprehensively explored the role of macrophage-related genes in human HCCs from multiple single-cell and bulk RNA sequencing datasets. Unsupervised clustering was performed to cluster the macrophage marker genes (MMGs). GSVA and functional enrichment analysis were used to elucidate the functional differences among the MMG-associated clusters. Subsequently, a component analysis algorithm was used to construct a Macrosig score, and the prognosis, biological characteristics, mutation profile, TME cell infiltration status and drug response of patients with different Macrosig scores were further analysed. Results: We identified 13 MMGs in 574 HCC samples, based on which three MMG-associated clusters were defined. Overall survival time, clinicopathological features and immune infiltration scores differed among the different clusters. On this basis, 12 hub genes were identified among these clusters; subsequently, a scoring system was constructed to determine the Macrosig score. Importantly, patients with low-Macrosig scores, characterized by increased immune infiltration, increased mutation frequency and increased immune checkpoint expression, including CTLA-4, LAG3, PDCD1 and TIGIT, exhibited enhanced efficacy of immunotherapy when validated in an external database. Moreover, a low-Macrosig score indicates increased sensitivity to AZD.2281, A.443654, ABT.263, ABT.888, AG.014699 and ATRA, while a high Macrosig score indicates increased sensitivity to AZD6482, AKT inhibitor VIII, AS601245, AZ628, AZD.0530 and AZD6244. Conclusions: A novel scoring system was constructed to guide more effective prognostic evaluation and tailoring therapeutic regimens for HCC patients.

Alterations in gut microbiome and metabolomics in chronic hepatitis B infection-associated liver disease and their impact on peripheral immune response.

Gut dysbiosis has been reported in chronic hepatitis B (CHB) infection, however its role in CHB progression and antiviral treatment remains to be clarified. Herein, the present study aimed to characterize gut microbiota (GM) in patients with chronic hepatitis B virus infection-associated liver diseases (HBV-CLD) by combining microbiome with metabolome analyses and to evaluate their effects on peripheral immunity. Fecal samples from HBV-CLD patients (n = 64) and healthy controls (n = 17) were collected for 16s rRNA sequencing. Fecal metabolomics was measured with untargeted liquid chromatography-mass spectrometry in subgroups of 58 subjects. Lineage changes of peripheral blood mononuclear cells (PBMCs) were determined upon exposure to bacterial extracts (BE) from HBV-CLD patients. Integrated analyses of microbiome with metabolome revealed a remarkable shift of gut microbiota and metabolites in HBV-CLD patients, and disease progression and antiviral treatment were found to be two main contributing factors for the shift. Concordant decreases in Turicibacter with 4-hydroxyretinoic acid were detected to be inversely correlated with serum AST levels through host-microbiota-metabolite interaction analysis in cirrhotic patients. Moreover, depletion of E.hallii group with elevated choline was restored in patients with 5-year antiviral treatment. PBMC exposure to BE from non-cirrhotic patients enhanced expansion of T helper 17 cells; however, BE from cirrhotics attenuated T helper 1 cell count. CHB progression and antiviral treatment are two main factors contributing to the compositional shift in microbiome and metabolome of HBV-CLD patients. Peripheral immunity might be an intermediate link in gut microbe-host interplay underlying CHB pathogenesis.

Integrated analyses of microbiome with metabolomics revealed a remarkable shift of gut microbiota and metabolites in HBV-CLD patients. Disease progression and entecavir treatment were found to be two main contributing factors for the shift. Novel host-microbiota-metabolite interplay was investigated (red, positive correlation; blue, negative correlation). Ex vivo results showed that exposure of PBMCs to BE from non-cirrhotic patients promoted expansion of T helper 17 cells whilst BE from cirrhotic patients attenuated T helper 1 cell count, suggesting peripheral immunity may be one of mechanisms by which overall bacterial products exert profibrotic effects and have an impact on prognosis of HBV-CLD patients. Our research confers new insights into the role of gut dysbiosis and metabolomics in the pathogenesis of HBV-CLD, and underscores that disrupted peripheral immunity homeostasis during the microbe-host interplay may contribute to fibrosis progression in HBV-CLD. CHB, chronic hepatitis B (treatment-naive); Crrh, cirrhosis; ETV, entecavir; HBV-CLD, chronic hepatitis B virus infection-associated liver diseases; HCs, healthy controls; MCFAs, medium chain fatty acids; NC, non-cirrhosis; Th1, T helper 1; Th17, T helper 17.Abbreviations: ALB, albumin; ALP, alkaline phosphatase; ANOISM, analysis of similarities; AST, aspartate aminotransferase; BE, bacterial extracts; BMI, body mass index; CC, compensated cirrhosis; CHB, chronic hepatitis B; DB, direct bilirubin; DC, decompensated cirrhosis; DCA, deoxycholic acid; ETV, entecavir; FDR, false discovery rate; GGT, γ-glutamyl transpeptidase; GM, gut microbiota; HBV, hepatitis B virus; HBV-CLD, chronic hepatitis B virus infection-associated liver diseases; HCs, healthy controls; HCC, hepatocellular carcinoma; LC-MS, liquid chromatography-mass spectrometry; LRE, liver-related events; LS, liver stiffness; ImP, imidazole propionate; IQR, interquartile range; MCFAs, medium chain fatty acids; OCT, organic cation transporter; OPLS-DA, orthogonal partial least square discriminant analysis; PBMCs, peripheral blood mononuclear cells; PERMANOVA, permutational multivariate analysis of variance; PLS-DA, partial least square discriminant analysis; PCA, principal component analysis; PcoA, principal coordinates analysis; PT, prolonged prothrombin time; SDs, standard deviations; TB, total bilirubin; Tregs, regulatory T cells; Th1, T helper 1; Th17, T helper 17.

Positive consequences of splenectomy for patients with schistosomiasis-induced variceal bleeding.

BACKGROUND: Patients with hepatic schistosomiasis are at high risk of gastroesophageal variceal bleeding, which is highly torrential and life threatening. This study aimed to assess the effects of splenectomy on patients with schistosomiasis-induced variceal bleeding, especially those influences related to overall survival (OS) rate. METHODS: From January 2005 to December 2018, 112 patients with schistosomiasis-induced varices were enrolled. In that period, all the patients with hepatic schistosomiasis who received endoscopic treatment for primary and secondary prophylaxis of gastroesophageal variceal bleeding were found eligible. The patients were divided into splenectomized group (n = 44, 39.3%) and control group (n = 68, 60.7%). RESULTS: Multivariate regression analysis of OS showed that splenectomy, hepatic carcinoma, and times of endoscopic treatment were independent prognostic factors for OS. Kaplan-Meier analysis revealed that the 5-year OS rate was 82.7% in splenectomized group versus 53.2% in control group (P = 0.037). The rate of no recurrence of variceal bleeding during 5-year (56.8% vs. 47.7%, P = 0.449) indicated that there was no significant difference between the two groups. Patients who received splenectomy had increased risk of portal vein thrombosis (52.3% vs. 29.4%, P = 0.012) and decreased proportion of severe ascites (20.5% vs 50.0%, P = 0.002). CONCLUSION: Splenectomy prior to endoscopic treatment provides a superior long-term survival for patients with schistosomiasis-induced variceal bleeding.