Review of recent research on hepatitis C therapy for 54th annual meeting of the American association for the study of liver diseases

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron sublineages BA.2.12.1, BA.4 and BA.5 exhibit higher transmissibility than the BA.2 lineage1. The receptor binding and immune-evasion capability of these recently emerged variants require immediate investigation. Here, coupled with structural comparisons of the spike proteins, we show that BA.2.12.1, BA.4 and BA.5 (BA.4 and BA.5 are hereafter referred collectively to as BA.4/BA.5) exhibit similar binding affinities to BA.2 for the angiotensin-converting enzyme 2 (ACE2) receptor. Of note, BA.2.12.1 and BA.4/BA.5 display increased evasion of neutralizing antibodies compared with BA.2 against plasma from triple-vaccinated individuals or from individuals who developed a BA.1 infection after vaccination. To delineate the underlying antibody-evasion mechanism, we determined the escape mutation profiles2, epitope distribution3 and Omicron-neutralization efficiency of 1,640 neutralizing antibodies directed against the receptor-binding domain of the viral spike protein, including 614 antibodies isolated from people who had recovered from BA.1 infection. BA.1 infection after vaccination predominantly recalls humoral immune memory directed against ancestral (hereafter referred to as wild-type (WT)) SARS-CoV-2 spike protein. The resulting elicited antibodies could neutralize both WT SARS-CoV-2 and BA.1 and are enriched on epitopes on spike that do not bind ACE2. However, most of these cross-reactive neutralizing antibodies are evaded by spike mutants L452Q, L452R and F486V. BA.1 infection can also induce new clones of BA.1-specific antibodies that potently neutralize BA.1. Nevertheless, these neutralizing antibodies are largely evaded by BA.2 and BA.4/BA.5 owing to D405N and F486V mutations, and react weakly to pre-Omicron variants, exhibiting narrow neutralization breadths. The therapeutic neutralizing antibodies bebtelovimab4 and cilgavimab5 can effectively neutralize BA.2.12.1 and BA.4/BA.5, whereas the S371F, D405N and R408S mutations undermine most broadly sarbecovirus-neutralizing antibodies. Together, our results indicate that Omicron may evolve mutations to evade the humoral immunity elicited by BA.1 infection, suggesting that BA.1-derived vaccine boosters may not achieve broad-spectrum protection against new Omicron variants. 

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BA.2.12.1, BA.4 and BA.5 escape antibodies elicited by Omicron infection

/pdf/ba-2-12-1-ba-4-and-ba-5-escape-antibodies-elicited-by-10nx8bt6.pdf

It has been recognized that cancer is not merely a disease of tumor cells, but a disease of imbalance, in which stromal cells and tumor microenvironment play crucial roles. Extracellular matrix (ECM) as the most abundant component in tumor microenvironment can regulate tumor cell behaviors and tissue tension homeostasis. Collagen constitutes the scaffold of tumor microenvironment and affects tumor microenvironment such that it regulates ECM remodeling by collagen degradation and re-deposition, and promotes tumor infiltration, angiogenesis, invasion and migration. While collagen was traditionally regarded as a passive barrier to resist tumor cells, it is now evident that collagen is also actively involved in promoting tumor progression. Collagen changes in tumor microenvironment release biomechanical signals, which are sensed by both tumor cells and stromal cells, trigger a cascade of biological events. In this work, we discuss how collagen can be a double-edged sword in tumor progression, both inhibiting and promoting tumor progression at different stages of cancer development.

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Collagen as a double-edged sword in tumor progression

Interactions between immune and malignant cells have been known to have clinical relevance for decades. The potential for immune control is now being therapeutically enhanced with checkpoint inhibitors and other novel agents to improve outcomes in cancer. The importance of the immune infiltrate as a prognostic marker is increasingly relevant. In this minireview, we present an overview of the immune infiltrate and its spatial organisation, and summarise the prognostic value of immune cells in different cancer types. International collaborative efforts are standardising histopathologic reporting of the immune infiltrate, to allow application of these parameters in the clinical and research settings. In general terms, a ‘pro-inflammatory’ tumour microenvironment and infiltrating CD8-expressing T lymphocytes are associated with improved clinical outcomes in a broad range of tumour types. The inhibitory function of other immune cells, for example, myeloid-derived suppressor cells and regulatory T cells, appear to have a major role in disrupting the capacity for the immune control of cancers.

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HYPE or HOPE: the prognostic value of infiltrating immune cells in cancer

Purpose 
Tumor-infiltrating FoxP3+ T cells have been reported in various human tumors, which impaired cell-mediated immunity and promoted disease progression. However, its prognostic value for survival in patients with different gastrointestinal cancers [hepatocellular carcinoma (HCC), colorectal cancer (CRC), gastric cancer (GC)] remains controversial.


Methods 
Relevant literature was searched using PubMed, Embase, Cochrane, Ovid Medline and Chinese wanfang databases. A meta-analysis was conducted to estimate pooled survival and recurrence ratios. The odds ratio (OR) and 95% confidence intervals (CI) were calculated employing fixed- or random-effects models depending on the heterogeneity of the included trials.


Results 
For HCC and GC, the overall survival at 1, 3 and 5-year of high FoxP3+ T cells infiltration patients were lower than low FoxP3+ T cells infiltration patients (P 0.05).


Conclusions 
Our findings suggested that tumor-infiltrating FoxP3+ T cells were a factor for a poor prognosis for HCC and GC, but a good prognosis for CRC.

/pdf/prognostic-value-of-tumor-infiltrating-foxp3-t-cells-in-1qt1vroj2t.pdf

Prognostic Value of Tumor-Infiltrating FoxP3+ T Cells in Gastrointestinal Cancers: A Meta Analysis

An increasing amount of evidence indicates that the inhibition of β adrenergic signaling can result in the inhibition of tumor growth. However, the role of propranolol in liver cancer and the underlying mechanism remain to be elucidated. The present study aimed to investigate the role of propranolol in liver cancer cell lines and provide evidence for further clinical study. Propranolol was added at different concentrations to HepG2 and HepG2.2.15 liver cancer cells and HL-7702 normal human liver cells. The proliferation of the cell lines was monitored by live-cell imaging at a range of time intervals. Immunofluorescence using DAPI and Hoechst 33342/propidium iodide (PI) staining, Annexin V-FITC/PI double-staining flow cytometry, western blotting and reverse transcription-quantitative polymerase chain reaction were used to investigate the effect of propranolol on liver cancer cell apoptosis. The proliferation of HepG2 and HepG2.2.15 cells was inhibited by 40 and 80 µmol/l propranolol. However, the proliferation of HL-7702 cells was not affected by <160 µmol/l propranolol. Propranolol treatment decreased the expression of adrenergic receptor β-2 to a greater extent than adrenergic receptor β-1, and induced apoptosis in the liver cancer cells. The apoptotic rates of HepG2 and HepG2.2.15 cells increased following treatment with propranolol, while the apoptotic rate of HL-7702 cells was not affected. Propranolol promoted poly (ADP-ribose) polymerase cleavage and decreased the expression of full-length caspase-3 in liver cancer cell lines; it induced S-phase arrest in HepG2 and HepG2.2.15 cell lines, while HL-7702 cells were arrested at the G0/G1 phase of the cell cycle. Thus, it was demonstrated that propranolol inhibited proliferation, promoted apoptosis and induced S-phase arrest in HepG2 and HepG2.2.15 cells.

/pdf/propranolol-suppresses-the-proliferation-and-induces-the-idx7pynm51.pdf

Propranolol suppresses the proliferation and induces the apoptosis of liver cancer cells.

Background

Recent studies have focused on regulatory T cells (Tregs) in chronic hepatitis B (CHB) and hepatocellular carcinoma (HCC) and they were also conducted independently of each other.



Aims

This study tried to characterize Tregs in blood and tumour infiltration, and to explore the correlations between Tregs and the context of chronic hepatitis B in HCC patients.



Methods

The liver-resident Tregs and CD8+ T cells on core biopsy were investigated using immunohistochemistry staining in individuals (n = 209) with CHB (n = 47), HCC (n = 137) or healthy controls (n = 25). Circulating Tregs were detected in the above patients with CHB (n = 27) or HCC (n = 101) by flow cytometry.



Results

The number of tumour-infiltrating and circulating FoxP3+ Tregs was significantly high in patients with CHB (P < 0.001). However, there were fewer intratumoural Tregs in patients with advanced HCC than those in patients with early stage HCC (P = 0.043); In contrast, the circulating Tregs frequency increased during the progression of HCC (P = 0.024). Increased tumour-infiltrating and circulating FoxP3+ Tregs were associated with poor overall survival (P = 0.041, 0.002 respectively) and a shorter time to recurrence (P = 0.049, 0.002 respectively) in patients with early stage HCC. Tumour-infiltrating Foxp3 +  Tregs were related to chronic hepatitis B natural history in HCC (P = 0.012). Neither tumour-infiltrating CD8+ T cells nor balance of intratumoural Tregs and CD8+ T cells correlated with prognosis of HCC.



Conclusions

Increased Foxp3+ Tregs may represent a prognostic predictor in patients with early stage HCC. The CHB natural history influenced density of tumour-infiltrating Tregs in hepatocellular carcinoma patients with chronic hepatitis B viruses infection.

Foxp3+ regulatory T cells are associated with the natural history of chronic hepatitis B and poor prognosis of hepatocellular carcinoma.

Background
Conflicting results have been obtained for the association between two common polymorphisms (C282Y, H63D) of human HFE (hereditary hemochromatosis) gene and the risks of the liver diseases, including non-alcoholic fatty liver disease (NAFLD), liver cirrhosis and hepatocellular carcinoma (HCC).

/pdf/association-between-the-hfe-c282y-h63d-polymorphisms-and-the-3g4s8qy3qn.pdf

Association between the HFE C282Y, H63D Polymorphisms and the Risks of Non-Alcoholic Fatty Liver Disease, Liver Cirrhosis and Hepatocellular Carcinoma: An Updated Systematic Review and Meta-Analysis of 5,758 Cases and 14,741 Controls.

Aims: Thermal ablation can evoke an immune response, which may have effects on the prognosis of patients with hepatocellular carcinoma (HCC). Our aim is to investigate the changes of circulating T-cell subsets after microwave ablation (MWA) and to explore the risk factors of tumor recurrence in patients with hepatitis B virus (HBV)-related HCC. Methods: Thirty patients with HBV-related HCC were enrolled in this study. The blood samples were collected both before and after MWA (24 h, 72 h, and 1 month after MWA). The distributions of Th17 cells, regulatory Treg-cells, CD4+ T-cells, CD8+ T-cells, and CD3+ T-cells were determined by flow cytometer. The potential-related factors of tumor recurrence were analyzed by logistic regression. Results: The levels of circulating T-cell subsets, except for Th17 cells, were relatively stable after MWA. The frequency of Th17 cells increased from 3.98% ± 2.40% before treatment to 5.53% ±3.27% 24 h after treatment. Eight of 30 patients had a tumor recurrence. The results of logistic regression suggested that among 11 candidates, only the level of Th17 cells was the risk factor of tumor recurrence. To remove the interference from other factors, seven patients with tumor(s) >3 cm or alpha-fetoprotein >400 ng/mL were excluded in another parallel logistic regression. The results of such regression clearly demonstrated that circulating Th17 cells is indeed a related factor of tumor recurrence. Conclusions: Thermal ablation may evoke a transitional immune response by increasing the frequency of Th17 cells. Patients with high levels of baseline circulating Th17 cells, instead of the transient elevation of Th17 cells induced by MWA, are at the risk of tumor recurrence.

Fengmei Wang

Papers

Prognostic Value of Tumor-Infiltrating FoxP3+ T Cells in Gastrointestinal Cancers: A Meta Analysis

Propranolol suppresses the proliferation and induces the apoptosis of liver cancer cells.

Foxp3+ regulatory T cells are associated with the natural history of chronic hepatitis B and poor prognosis of hepatocellular carcinoma.

Association between the HFE C282Y, H63D Polymorphisms and the Risks of Non-Alcoholic Fatty Liver Disease, Liver Cirrhosis and Hepatocellular Carcinoma: An Updated Systematic Review and Meta-Analysis of 5,758 Cases and 14,741 Controls.

Dynamic changes of T-cell subsets and their relation with tumor recurrence after microwave ablation in patients with hepatocellular carcinoma