Proton pump inhibitor therapy is associated with reduced survival following first-time transarterial chemoembolization in patients with hepatocellular carcinoma.

BACKGROUND AND AIMS: Several studies have reported associations of proton pump inhibitor (PPI) treatment with the incidence of complications and even increased mortality in patients with liver cirrhosis. Up to now, there are no studies on the impact of PPI treatment in patients with hepatocellular carcinoma (HCC). Therefore, the aim of our study was to investigate the prognostic effects of PPI treatment in a cohort of patients with HCC treated by transarterial chemoembolization (TACE). METHODS: Three hundred fifty-eight patients with HCC that received first-time TACE were included in a retrospective analysis. We explored effects of PPI treatment using uni- and multivariable regression models. RESULTS: One hundred sixty-seven of the 358 patients (46.6%) received PPI treatment. Median transplant-free survival after TACE was significantly lower in patients treated with PPIs compared to patients without PPI treatment [16.0 (10.7-21.3) months vs. 26 (22.2-29.8) months, P = 0.006]. Importantly, PPI treatment remained a significant prognostic factor for reduced survival after adjustment for patient demographics, tumor stadium and liver function [hazard ratio (HR) 1.40, 95% confidence interval (CI) 1.09-1.78, P = 0.005]. We observed a dose-dependent association of PPI treatment with survival: A higher daily PPI dose was an independent prognostic factor for reduced survival (HR 1.32, 95% CI 1.14-1.54, P < 0.001). Notably, 58.1% of patients receiving PPIs had no clear indication therefor. CONCLUSION: PPI treatment is associated with reduced survival in patients with HCC in a dose-dependent manner. Thus, indication for PPI treatment should be evaluated attentively in these patients. Further, prospective studies are needed to validate the findings of this study.

MAIT Cells in Viral Hepatitis and Liver Diseases.

Mucosal-associated invariant T (MAIT) cells are a group of unconventional T cells that have come into focus of researchers in the past years. They are abundant in humans and enriched in tissues like the liver. Their roles in physiological immune processes and in the context of infectious, autoimmune and malign diseases have been studied extensively. In this review, we summarize the current knowledge about MAIT cells in viral hepatitis and liver diseases.

Characterization of pre-existing and induced SARS-CoV-2-specific CD8+ T cells.

Emerging data indicate that SARS-CoV-2-specific CD8+ T cells targeting different viral proteins are detectable in up to 70% of convalescent individuals1-5. However, very little information is currently available about the abundance, phenotype, functional capacity and fate of pre-existing and induced SARS-CoV-2-specific CD8+ T cell responses during the natural course of SARS-CoV-2 infection. Here, we define a set of optimal and dominant SARS-CoV-2-specific CD8+ T cell epitopes. We also perform a high-resolution ex vivo analysis of pre-existing and induced SARS-CoV-2-specific CD8+ T cells, applying peptide-loaded major histocompatibility complex class I (pMHCI) tetramer technology. We observe rapid induction, prolonged contraction and emergence of heterogeneous and functionally competent cross-reactive and induced memory CD8+ T cell responses in cross-sectionally analyzed individuals with mild disease following SARS-CoV-2 infection and three individuals longitudinally assessed for their T cells pre- and post-SARS-CoV-2 infection. SARS-CoV-2-specific memory CD8+ T cells exhibited functional characteristics comparable to influenza-specific CD8+ T cells and were detectable in SARS-CoV-2 convalescent individuals who were seronegative for anti-SARS-CoV-2 antibodies targeting spike (S) and nucleoprotein (N). These results define cross-reactive and induced SARS-CoV-2-specific CD8+ T cell responses as potentially important determinants of immune protection in mild SARS-CoV-2 infection.

TOX defines the degree of CD8+ T cell dysfunction in distinct phases of chronic HBV infection.

OBJECTIVE: Chronic hepatitis B virus (HBV) infection is characterised by HBV-specific CD8+ T cell dysfunction that has been linked to Tcell exhaustion, a distinct differentiation programme associated with persisting antigen recognition. Recently, Thymocyte Selection-Associated High Mobility Group Box (TOX) was identified as master regulator of CD8+ T cell exhaustion. Here, we addressed the role of TOX in HBV-specific CD8+ T cell dysfunction associated with different clinical phases of infection. DESIGN: We investigated TOX expression in HBV-specific CD8+ T cells from 53 HLA-A*01:01, HLA-A*11:01 and HLA-A*02:01 positive patients from different HBV infection phases and compared it to hepatitis C virus (HCV)-specific, cytomegalovirus (CMV)-specific, Epstein-Barr virus (EBV)-specific and influenza virus (FLU)-specific CD8+ T cells. Phenotypic and functional analyses of virus-specific CD8+ T cells were performed after peptide-loaded tetramer-enrichment and peptide-specific expansion. RESULTS: Our results show that TOX expression in HBV-specific CD8+ T cells is linked to chronic antigen stimulation, correlates with viral load and is associated with phenotypic and functional characteristics of T-cell exhaustion. In contrast, similar TOX expression in EBV-specific and CMV-specific CD8+ T cells is not linked to T-cell dysfunction suggesting different underlying programmes. TOX expression in HBV-specific CD8+ T cells is also affected by targeted antigens, for example, core versus polymerase. In HBV-specific CD8+ T cells, TOX expression is maintained after spontaneous or therapy-mediated viral control in chronic but not self-limiting acute HBV infection indicating a permanent molecular imprint after chronic but not temporary stimulation. CONCLUSION: Our data highlight TOX as biomarker specific for dysfunctional virus-specific CD8+ T cells in the context of an actively persisting infection.

CD4+ T cell responses in human viral infection: lessons from hepatitis C.

Liver disease as a result of chronic hepatitis C virus (HCV) infection is a global problem. While some HCV infections resolve spontaneously, viral persistence associates with compromised T cell immunity. In this issue of the JCI, Chen et al. and Coss et al. explored virus-specific CD4+ T cell response during HCV infection. Both studies evaluated the HCV-specific T cells of patients with different courses of infection. Chen et al. revealed that initial CD4+ T cell responses are similar during early infection and that T cell failure resulted from loss of the virus-specific T cells themselves. Coss et al. showed that HCV-specific CD4+ T cells temporarily recovered in some women following childbirth. These studies contribute to our understanding of CD4+ T cell functionality during different natural courses of infection, with the notable implication that restoring CD4+ T cell immunity might contribute to controlling HCV infection.

Unique and Common Features of Innate-Like Human Vδ2+ γδT Cells and Mucosal-Associated Invariant T Cells.

Mucosal-associated invariant T (MAIT) cells are innate-like T cells abundant in humans that can be activated in a TCR-independent manner by inflammatory and antiviral cytokines. In humans, the capacity for TCR-independent activation is functionally linked to a transcriptional program that can be identified by the expression of the C-type lectin receptor, CD161. In addition to MAIT cells, it has been demonstrated that a subset of γδT cells expresses CD161 and can be activated by TCR-independent cytokine stimulation. In this study, we sought to clarify the nature of cytokine-responsive human γδT cells. We could link CD161 expression on Vδ2+ versus Vδ1+ γδT cells to the observation that Vδ2+ γδT cells, but not Vδ1+ γδT cells, robustly produced IFN-γ upon stimulation with a variety of cytokine combinations. Interestingly, both CD161+ and CD161- Vδ2+ γδT cells responded to these stimuli, with increased functionality within the CD161+ subset. This innate-like responsiveness corresponded to high expression of PLZF and IL-18Rα, analogous to MAIT cells. Vδ2+ γδT cells in human duodenum and liver maintained a CD161+ IL-18Rα+ phenotype and produced IFN-γ in response to IL-12 and IL-18 stimulation. In contrast to MAIT cells, we could not detect IL-17A production but observed higher steady-state expression of Granzyme B by Vδ2+ γδT cells. Finally, we investigated the frequency and functionality of γδT cells in the context of chronic hepatitis C virus infection, as MAIT cells are reduced in frequency in this disease. By contrast, Vδ2+ γδT cells were maintained in frequency and displayed unimpaired IFN-γ production in response to cytokine stimulation. In sum, human Vδ2+ γδT cells are a functionally distinct population of cytokine-responsive innate-like T cells that is abundant in blood and tissues with similarities to human MAIT cells.

Hepatitis B Virus-Infected HepG2hNTCP Cells Serve as a Novel Immunological Tool To Analyze the Antiviral Efficacy of CD8+ T Cells In Vitro.

CD8(+) T cells are the main effector lymphocytes in the control of hepatitis B virus (HBV) infection. However, limitations of model systems, such as low infection rates, restrict mechanistic studies of HBV-specific CD8(+) T cells. Here, we established a novel immunological cell culture model based on HBV-infected HepG2(hNTCP) cells that endogenously processed viral antigens and presented them to HBV-specific CD8(+) T cells. This induced cytolytic and noncytolytic CD8(+) T-cell effector functions and reduction of viral loads.