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Hepatocellular carcinoma (HCC) is an immunogenic malignancy, which exhibits low responsiveness to programmed cell death protein‑1 (PD‑1)/programmed death ligand‑1 (PD‑L1) antibodies. Therefore, the identification of novel immunotherapeutic targets to treat HCC is imperative. Systematic characterization of the HCC tumor microenvironment (TME) can provide novel insight into additional therapeutic approaches. In the present study, the RNA‑sequencing (RNA‑seq) data of 360 patients with HCC were integrated from The Cancer Genome Atlas to assess the expression of membrane spanning 4‑domains A1 ( MS4A1 ; encoding CD20) in tumors and normal liver tissues. Immunofluorescence and multiplex tissue fluorescence analyses were performed and combined with flow cytometry staining to measure CD20/CD19 expression at the protein level. In addition, published single cell RNA‑seq data of CD45 + cells were derived from 16 treatment‑naïve patients from Beijing Shijitan Hospital with HCC to illustrate the characteristics of CD19 + B cells. The results indicated that the HCC TME included nuclear receptor subfamily 4 group A member 2 +  (NR4A2) B cells. Patients with HCC and high density of intratumoral B cells demonstrated compromised antitumor immunity manifested by low percentages of cytotoxic CD8 + T cells and high density of regulatory T cells. Furthermore, PD‑L1 expression was significantly correlated with the B cell signature marker CD20. The present study indicated that tumor‑infiltrating B cells may play a negative role in antitumor immunity and serve as a promising target for HCC immunotherapy, alone or in combination with anti‑PD‑L1/PD‑1 antibodies.

The molecular mechanisms whereby CD8 + T cells become "exhausted" in the tumor microenvironment remain unclear. Programmed death ligand-1 (PD-L1) is upregulated on tumor cells and PD-1-PD-L1 blockade has significant efficacy in human tumors; however, most patients do not respond, suggesting additional mechanisms underlying T cell exhaustion. B7 superfamily member 1 (B7S1), also called B7-H4, B7x, or VTCN1, negatively regulates T cell activation. Here we show increased B7S1 expression on myeloid cells from human hepatocellular carcinoma correlated with CD8 + T cell dysfunction. B7S1 inhibition suppressed development of murine tumors. Putative B7S1 receptor was co-expressed with PD-1 but not T cell immunoglobulin and mucin-domain containing-3 (Tim-3) at an activated state of early tumor-infiltrating CD8 + T cells, and B7S1 promoted T cell exhaustion, possibly through Eomes overexpression. Combinatorial blockade of B7S1 and PD-1 synergistically enhanced anti-tumor immune responses. Collectively, B7S1 initiates dysfunction of tumor-infiltrating CD8 + T cells and may be targeted for cancer immunotherapy., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: To study the clinical features of nonalcoholic fatty liver disease (NAFLD)-associated hepatocellular carcinoma (HCC)., Methods: The clinical manifestations, imaging features, pathological subtypes and treatment outcome of two cases with NAFLD-associated HCC were analyzed., Results: In these two cases, both were young, obese male patients, with contrast enhanced CT scan of hemangioma-like features. They had undergone surgical resection and both were reported as well-differentiated HCC pathologically. They were followed-up respectively up to 46 and 36 months post-operatively with no evidence of recurrence or metastasis., Conclusions: NAFLD-associated HCC has different radiological presentations from typical HCC. Incidental finding of any liver occupying lesions in NAFLD patients should raise immediate clinical attention.

Objective: To investigate the role of CCL20/CCR6/Th17 axis in vascular invasion and metastasis of primary hepatocellular carcinoma (HCC)., Methods: Expression levels of CCL20 mRNA in the normal human liver cell line L-02, and human hepatocellular carcinoma cell lines Hep3B, Huh7 and HepG2 were quantified by using SYBR green real time PCR. CCL20 secretions from these cell lines were quantified by using ELISA. The chemotactic effect of HCC cell line Hep3B on human peripheral blood mononuclear cells was determined by using transwell chemotaxis assay. Pre-therapy serum levels of IL-1α, IL-1β, IL-6, IL-8, IL-10, IL-17, IL-23, IFN-γ, TNF-α and CCL20 in 93 patients with HCC were measured by using 9-plex array and ELISA. All the patients were chronic hepatitis B virus associated HCC, and 51 cases were those with vascular invasion and metastasis (metastasis group) and 42 cases were not (non-metastasis group). CCL20 and CCR6 mRNA expressions in the HCC and tumor-adjacent tissues were determined by using SYBR Green real time PCR in 41 patients, among them, 20 cases were from the group of patients with metastasis and 21 cases were from the group of patients without metastasis. The CCL20 expression was further determined by immunohistochemistry., Results: The HCC cell lines expressed and secreted higher amount of CCL20, which effectively recruited CCR6(+) T cells. Pre-therapy serum levels of CCL20 in 93 HCC patients were (38.2 ± 28.4)pg/ml, significantly increased than those with benign hepatic hemangiomas [(7.8 ± 17.8)pg/ml, P < 0.01]. In addition, the serum levels of CCL20 were positively correlated with the tumor diameters in HCC patients (r = 0.32, P = 0.0018). CCL20 was dominantly expressed in the cytoplasm in HCC cells, and it was also expressed by some infiltrating immune cells. The mRNA expression levels of CCL20 of the tumor tissues were significantly higher than that in the tumor-adjacent tissues (P < 0.05). Multivariate logistic regression analysis showed that serum levels of IL-17 and CCL20 were independent risk factors of metastasis in HCC patients (P < 0.05 for both). CCL20 mRNA showed no statistically significant differences between patients with metastasis and without metastasis in both tumor tissues and tumor-adjacent tissues (P > 0.05 for both). But the patients with metastasis showed significantly higher expressions of CCR6 both in their tumor [5.75 (1.79, 19.13)]and tumor-adjacent tissues [7.99 (4.49, 19.54)] than those with non-metastasis [1.69 (0.76, 2.87) and 3.58 (1.84, 4.32), P < 0.05 for both]., Conclusion: CCL20/CCR6/Th17 axis may promote vascular invasion and metastasis hepatocellular carcinoma.

Background: Although radiotherapy (RT) provides potential benefits for patients with hepatocellular carcinomas (HCCs) that are unsuitable for operation, the specific role of adjuvant RT in HCC after hepatectomy remains ill defined. The current study's aim was to evaluate the safety and efficacy of adjuvant RT for centrally located HCCs after narrow-margin (<1 cm) hepatectomy., Study Design: The study included 119 patients with centrally located HCCs who underwent narrow-margin hepatectomy between July 2007 and March 2012. Patients were prospectively randomized to receive adjuvant RT (n = 58) or were assigned to a control group (n = 61). Surgical outcomes, safety, and survival rates were evaluated., Results: Hepatectomy was successfully performed in all patients. No cases of radiation-induced liver disease were observed. One-, 3-, and 5-year recurrence-free survival rates were 78.1%, 56.5%, and 36.9% in the adjuvant RT group and 72.4%, 40.1%, and 16.0% in the control group, respectively (p = 0.06, log-rank test). Corresponding overall survival rates were 96.2%, 72.6%, 48.4%, and 89.6%, 74.5%, 37.2%, respectively (p = 0.48, log-rank test). One-, 3-, and 5-year recurrence-free survival rates in patients with small-diameter tumors (≤5 cm) were 88.8%, 67.4%, 42.9% in the adjuvant RT group and 82.3%, 42.9%, 21.5% in the control group (p = 0.03, log-rank test). Corresponding overall survival rates were 97.5%, 75.3%, 75.3%, and 94.7%, 84.1%, 65.4%, respectively (p = 0.92, log-rank test)., Conclusions: Adjuvant RT for centrally located HCCs after narrow-margin hepatectomy was technically feasible and relatively safe. No significant between-group difference was observed in recurrence-free and overall survival. The post-hoc subgroup comparison showed that adjuvant RT improved recurrence-free survival considerably, but not overall survival, in patients with small HCCs (≤5 cm). More in-depth studies are needed to validate this finding., (Copyright © 2014 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: This study aimed to clarify the risk factors for survival and recurrence of hepatocellular carcinoma (HCC) in a cohort of Chinese HCC patients after hepatectomy and to compare 6 developed staging systems., Methods: A retrospective analysis was performed on 165 consecutive patients. The Kaplan-Meier method was used to calculate survival. Postoperative prognostic factors were evaluated using univariate and multivariate analyses. The overall predictive power of each staging system was evaluated by the area under the receiver operating characteristic curve., Results: The overall survival rates of 1, 3, and 5 years were 81.2%, 58.6%, and 56.7%, respectively, and the corresponding disease-free survival rates were 52.9%, 23.3%, and 15.5%, respectively. α-fetoprotein level and blood transfusion were correlated significantly with patients' overall survival, and portal vein thrombosis and tumor size (>5 cm) were correlated significantly with poor disease-free survival., Conclusions: The French staging system is better for predicting the prognosis of HCC patients receiving surgical treatment., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background and Aims: Primary hepatocellular carcinoma (HCC) is usually presented in inflamed fibrotic/cirrhotic liver with extensive lymphocyte infiltration. We examined the associations between the HCC early recurrence and alterations in serum levels of inflammatory cytokines., Methods: A cohort of 105 HCC patients with chronic hepatitis B virus infection were included. Pre-therapy, we quantified their serum concentrations of Th1-, Th2-, Th17-, Treg-related, and other cytokines that have been reported to be associated with poor prognosis in human cancers. IL17-producing T-cells were generated in vitro from HCC patients and co-cultured with HCC cell lines separated by a 0.4 µM transwell., Results: All the 105 cases of HCC patients had liver cirrhosis. The patients who suffered from HCC early recurrence had higher pre-therapy serum levels of IL17 and lower levels of IL10 than those who did not suffer from recurrence after curative hepatectomy. After adjustment for general tumor clinicopathological factors, elevated serum levels of IL17 (≥ 0.9 pg/ml) was found to be an independent risk factor for HCC early recurrence with a hazard ratio of 2.46 (95%CI 1.34-4.51). Patients with bigger tumors (>5 cm in diameter) and elevated serum levels of IL17 had the highest risk of early recurrence as compared to those with only one of these factors (P = 0.009) or without any (P<0.001). These factors showed similar effects on the HCC patient overall survival. Intrahepatic infiltrated T-cells in HCC patients were identified as the major IL17-producing cells. Proliferation of HCC cells, QGY-7703, was augmented QGY-7703, was augmented in the presence of IL17-producing T-cells. This effect diminished after neutralizing antibody against human IL17A or TNFα was included., Conclusion: Both tumors and IL17 from liver infiltrated T-cells contributed to HCC early recurrence and progression after curative resection. Pre-therapy serum IL17 levels may serve as an additional indicator for predicting high-risk patients.