Natural killer cell phenotype modulation and natural killer/T-cell interplay in nucleos(t)ide analogue-treated hepatitis e antigen-negative patients with chronic hepatitis B.

UNLABELLED: Natural killer (NK) and hepatitis B virus (HBV)-specific T cells are functionally impaired in chronic hepatitis B (CHB). Understanding to what extent nucleos(t)ide analogue (NUC) therapy can improve T- and NK-cell responses is important in the perspective of immunomonitoring strategies for a safe and earlier NUC withdrawal and of novel combination therapies based on modulation of antiviral immunity. To gain further insights into T/NK-cell interplay, we studied NK-cell phenotype and function in hepatitis B e antigen-negative chronic HBV patients either untreated (25) or NUC treated (36 hepatitis B surface antigen [HBsAg](+) and 10 HBsAg(-)/hepatitis B surface antibody [anti-HBs](+)). Interferon-gamma, interleukin-2, and tumor necrosis factor alpha (TNF-α) production by HBV-specific T cells was also analyzed in NUC-treated patients. NK cells from chronic naïve patients showed an "inflammatory" phenotype defined by increased expression of TNF-related apoptosis-inducing ligand (TRAIL), CD38, and Ki67 that significantly declined upon viremia suppression and alanine aminotransferase normalization induced by NUC therapy. Reversion to a quiescent NK-cell phenotype was associated with restoration of the HBV-specific T-cell function. T- and NK-cell responses showed an inverse correlation, with an opposite behavior in individual NUC-treated patients. NK-cell depletion as well as TRAIL and NKG2D pathway blockade induced a significant improvement of the HBV-specific T-cell function. CONCLUSIONS: NK cells can express regulatory activity on T cells in NUC-treated patients with prevalent inhibition of CD4 T cells, likely needed to limit persistent T-cell activation. NK-cell phenotype is modulated by NUC therapy and its reversion to quiescence mirrors efficient HBV-specific T-cell responses. Thus, changes of NK-cell phenotype may predict acquisition of antiviral control before anti-HBs seroconversion and represent the groundwork for future studies aimed at assessing whether NK phenotyping can be translated into the clinical practice to guide NUC suspension.

Antiviral intrahepatic T-cell responses can be restored by blocking programmed death-1 pathway in chronic hepatitis B.

BACKGROUND & AIMS: The antiviral function of peripheral hepatitis B virus (HBV)-specific T cells can be increased in patients with chronic hepatitis B by blocking the interaction of programmed death (PD)-1 with its ligand PD-L1. However, no information is available about the effects of this blockade on intrahepatic lymphocytes. We studied T-cell exhaustion and the effects of PD-1/PD-L1 blockade on intrahepatic and circulating HBV-specific T cells in patients with chronic hepatitis B. METHODS: A total of 42 patients with chronic HBV infection who underwent liver biopsy were studied. The ex vivo phenotype of peripheral and intrahepatic HBV-specific CD8(+) T cells was assessed by flow cytometry with class I tetramers and antibodies to T-cell differentiation molecules. Functional recovery was evaluated by analyzing expansion and production of interferon (IFN)-gamma and interleukin (IL)-2 after short-term incubation of T cells with HBV peptides in the presence of anti-PD-L1 or control antibodies. RESULTS: Intrahepatic HBV-specific CD8(+) cells expressed higher levels of PD-1 and lower levels of CD127 than their peripheral counterparts. Blockade of PD-1/PD-L1 interaction increased CD8(+) cell proliferation and IFN-gamma and IL-2 production by circulating intrahepatic lymphocytes, even though anti-PD-L1 had a stronger effect on intrahepatic compared with peripheral T cells. CONCLUSIONS: T-cell exhaustion by high antigen concentrations promotes HBV-specific T-cell dysfunction by affecting phenotype and function of peripheral and intrahepatic T cells. By restoring antiviral T-cell functions, not only in peripheral but also in intrahepatic lymphocytes, anti-PD-L1 might be a good therapeutic candidate for chronic HBV infection.

Tumor/stromal caveolin-1 expression patterns in pleural mesothelioma define a subgroup of the epithelial histotype with poorer prognosis.

OBJECTIVES: Malignant pleural mesothelioma (MPM) is a highly aggressive disease for which new prognostic biomarkers need to be identified. Caveolin-1 (CAV1), the most important member of caveolae, has been described as deregulated in MPM at the genomic level, but detailed histologic information on its distribution and prognostic role is still lacking. METHODS: A series of 131 MPMs (91 epithelial, 17 biphasic, and 23 sarcomatous histotype) were investigated for CAV1 expression with immunohistochemistry and correlated with clinical-pathologic variables and outcome. RESULTS: CAV1 was detected in neoplastic cells of 70 (77%) of 91 epithelial, 17 (100%) of 17 biphasic, and 23 (100%) of 23 sarcomatous MPMs. Furthermore, in the epithelial group, CAV1 expression in spindle-shaped stromal cells was detected in 61 (67%) of 91 cases. CONCLUSIONS: The presence of stromal CAV1 expression was associated with a worse patient outcome. In MPM, CAV1 is differentially expressed according to low- to high-grade histotypes. Furthermore, in the MPM epithelial group, additional stromal CAV1 expression is associated with a worse prognosis.

Restoration of HCV-specific T cell functions by PD-1/PD-L1 blockade in HCV infection: effect of viremia levels and antiviral treatment.

BACKGROUND/AIMS: HCV-specific T cells in acute hepatitis C with subsequent chronic evolution are dysfunctional and most of them express PD-1. The aim of the study was to investigate to what extent the antiviral T cell function can be restored by reversing T cell exhaustion by PD-1/PD-L1 blockade and to assess whether this restoration is favored by IFN-alpha treatment. METHODS: PD-1 and PD-L1 expression was studied on T cells and dendritic cells, respectively, of 14 patients with acute hepatitis C and different evolutions of infection. The effect of anti-PD-L1 was analyzed on proliferation, cytokine production and cytolytic activity of CD4 and CD8 T cells. RESULTS: While PD-1 expression dropped concurrently with spontaneous or IFN-alpha induced HCV-RNA decline, PD-L1 levels on dendritic cells increased during IFN-alpha treatment. Anti-PD-L1 antibodies improved expansion and cytokine production but not the cytolytic activity of HCV-specific T cells. This restoration tended to be greater at lower levels of viremia and PD-1 expression and during PEG-IFNalpha treatment. CONCLUSIONS: PD-1/PD-L1 blockade has an immunoregulatory activity which may synergize with the antiviral effect of IFN-alpha therapy and should be thus explored further in long-lasting chronic HCV infections in the perspective of improving the efficacy of available antiviral treatments.