UMLS:C0019204 - FACTA Search

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Query: UMLS:C0019204 (hepatocellular carcinoma)
71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cell death induction by cytotoxic T lymphocytes (CTLs) is an important thesis for the understanding of tumor immunotherapy. In the current study we investigated the molecular machinery of CTL-induced cell death in human hepatocellular carcinoma cell lines (HCC lines). CTLs prepared from human peripheral blood induced cell death in all tested HCC lines. As the CTL-induced death system, the effectiveness of Fas ligand/Fas and/or Perforin/Granzyme B systems has been suggested, whereas cell death induction by CTLs was shown independently on Fas expression in the current study. Using various tetrapeptide inhibitors for caspase and its associated factor, we additionally demonstrated that inhibitors for caspase 3 (Ac-DEVD-CHO) and caspase 8/granzyme B (Ac-IETD-CHO) suppressed CTL-induced cell death, but an inhibitor for Fas-activated serine proteinase, which acts for the caspase 3 activator, did not, suggesting that CTL-induced cell death was initiated by the Perforin/Granzyme B system, rather than the Fas ligand/Fas system. On the basis of our current results, we report here that the Perforin/Granzyme B system acts dominantly for the cell death induction of HCC lines.
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PMID:Cell death induction by CTL: perforin/granzyme B system dominantly acts for cell death induction in human hepatocellular carcinoma cells. 1104 57

Infection with hepatitis C virus (HCV) is characterized by inflammatory liver damage and a long viral persistence associated with an increased risk of developing hepatocellular carcinoma. Both in liver damage and in oncogenesis a disturbance of apoptosis has been implicated, although the underlying mechanisms in these apparently opposite processes are incompletely understood. HCV-triggered liver injury is mediated mainly by host immune mechanisms and eventually by direct cytopathic effects of HCV. Recent data shows that caspase activation, either triggered by death ligands, other cytokines, granzyme B or HCV proteins, is considerably upregulated in HCV-infected liver. Interestingly, caspase activation appears to correlate closely with the inflammatory response. Data about the role of single HCV proteins, either in cultured cells or transgenic animals models, however, are contradictory, as both pro- and anti-apoptotic effects have been observed. Nevertheless, apoptosis induction upon HCV infection may critically contribute to liver damage, while inhibition of apoptosis may result in HCV persistence and development of hepatocellular carcinoma.
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PMID:Apoptosis in hepatitis C virus infection. 1265 46

The association of a specific autoantibody response with distinct disease phenotypes is observed in both autoimmune diseases and cancer. Although the underlying mechanisms remain unclear, it is likely that unique properties of disease-specific autoantigens expressed in the relevant target cells play a role. It has recently been observed that the majority of autoantigens targeted across the spectrum of systemic autoimmune diseases (but not nonautoantigens) are selectively cleaved by the cytotoxic lymphocyte granule protease granzyme B (GB), generating unique fragments not observed during other forms of cell death. Although susceptibility of a molecule to cleavage by GB strongly predicts autoantigen status, the significance of this association is unclear. We used hepatocellular carcinoma and the hepatocellular carcinoma autoantigen, nucleophosmin/B23, as a model system to define the unique features of disease-specific autoantigens in the relevant disease microenvironment. These studies revealed a striking, selective susceptibility of B23 to cleavage by GB in extracts of neoplastic liver. The increased sensitivity of tumor B23 to proteolysis by GB was accompanied by slightly increased mobility on SDS/PAGE, altered subcellular localization, enrichment of an SDS-stable oligomeric form of B23, and recognition by a conformation-specific antibody detecting a B23 epitope ending at the GB cleavage site. In vitro studies demonstrated that this unique B23 conformation and resultant increased susceptibility to cleavage by GB arise when B23 translation is initiated at methionine-7. We propose that unique features of autoantigens in the disease-relevant microenvironment may regulate susceptibility to cleavage by GB and their selection by the specific autoimmune response.
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PMID:Unique conformation of cancer autoantigen B23 in hepatoma: a mechanism for specificity in the autoimmune response. 1451 47

In patients with hepatocellular carcinoma (HCC), natural killer (NK) cell activity decreases significantly, and the reduced activity may be associated with the progression of HCC. In this study we evaluated the effects of pulsing with interleukin (IL)-2 and/or IL-12 on the activation of freshly isolated peripheral blood lymphocytes (PBL) derived from patients with HCC. PBL obtained from 9 HCC patients, 4 liver cirrhosis patients, and 9 normal subjects were cultured in the presence of IL-2 and/or IL-12. After 24 h of incubation, the levels of interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha presented in the supernatants were determined by enzyme-linked immunosorbent assay (ELISA). The IFN-gamma and TNF-alpha production of PBL pulsed by a combination of IL-2 and IL-12 was significantly higher than those of PBL stimulated by either IL-2 or IL-12 alone. The mRNA encoding perforin, granzyme B, as well as IFN-gamma and TNF-alpha, were markedly enhanced in PBL stimulated with a combination of IL-12 and IL-2. The pulsing procedure of IL-12 in combination with IL-2 resulted in the increase of IFN-gamma and TNF-alpha, and the expression of perforin and granzyme B mRNA in PBL obtained from HCC patients, as well as in those obtained from normal subjects. These results indicate that adoptive immunotherapy based on PBL pulsed with a combination of IL-2 and IL-12 may be a promising adjunctive strategy for HCC treatment.
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PMID:Effects of pulsing procedure of interleukin-12 in combination with interleukin-2 on the activation of peripheral blood lymphocytes derived from patients with hepatocellular carcinoma. 1472 65

Expression of the granzyme B inhibitors, human proteinase inhibitor 9 (PI-9), or the murine orthologue, serine proteinase inhibitor 6 (SPI-6), confers resistance to CTL or NK killing by perforin- and granzyme-dependent effector mechanisms. In light of prior studies indicating that virally infected hepatocytes are selectively resistant to this CTL effector mechanism, the present studies investigated PI-9 and SPI-6 expression in hepatocytes and hepatoma cells in response to adenoviral infection and to cytokines produced during antiviral immune responses. Neither PI-9 nor SPI-6 expression was detected by immunoblotting in uninfected murine or human hepatocytes. Similarly, human Huh-7 hepatoma cells were found to express only very low levels of PI-9 relative to levels detected in perforin- and granzyme-resistant CTL or lymphokine-activated killer cells. Following in vivo adenoviral infection or in vitro culture with IFN-alphabeta or IFN-gamma, SPI-6 expression was induced in murine hepatocytes. Similarly, after culture with IFN-alpha, induction of PI-9 mRNA and protein expression was observed in human hepatocytes and Huh-7 cells. IFN-gamma and TNF-alpha also induced 4- to 10-fold higher levels of PI-9 mRNA expression in Huh-7 cells, whereas levels of mRNA encoding a related serine proteinase inhibitor, proteinase inhibitor 8, were unaffected by culture of Huh-7 cells with IFN-alpha, IFN-gamma, or TNF-alpha. These findings indicate that cytokines that promote antiviral cytopathic responses also regulate expression of the cytoprotective molecules, PI-9 and SPI-6, in hepatocytes that are potential targets of CTL and NK effector mechanisms.
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PMID:Antiviral cytokines induce hepatic expression of the granzyme B inhibitors, proteinase inhibitor 9 and serine proteinase inhibitor 6. 1512 37

Hepatocellular carcinoma (HCC) has a poor prognosis with limited therapeutic options. We propose that local immune responses in patients with HCC are held in check by tumor-infiltrating CD4(+)CD25(+) T-regulatory lymphocytes (T(reg) cells), which suppress the activity and proliferation of effector CD4(+) and CD8(+) T cells. The phenotype and cell cycle status of tumor-infiltrating lymphocytes (TILs) in HCC were analyzed via immunohistochemistry of sections from patients undergoing surgery for HCC and via flow cytometry of peripheral blood mononuclear cells and TILs isolated from patients with HCC. Circulating and tumor-infiltrating T-cell function and activation status were assessed via proliferation and flow cytometry. More than 96% of TILs were quiescent as measured via Mcm-2 or Ki-67 expression, while less than 10% of CD8(+) T cells expressed perforin or granzyme B. CD4(+)CD25(+) T(reg) cells comprised 8.7% (1.4-13.8) of TILs and always exceeded the proportion in distant nontumor tissue (2.4% [1.5-5.6]; P = .014). T(reg) cells isolated from HCC suppressed proliferation of autologous circulating CD4(+)CD25(-) cells and perforin expression and proliferation of autologous CD8(+) T cells. The proportion of circulating T(reg) cells in patients with HCC was similar in healthy controls (7.2% [1.2-23.3] and 9.2% [1.6-30.2], respectively), but the proportion of circulating T(reg) cells that were also transforming growth factor beta1(+) was elevated in HCC compared with controls (55.5% [8.2-73.9] and 2.0% [0-4.9], respectively; P = .003). In conclusion, TILs are compromised and contain a subpopulation of suppressive CD4(+)CD25(+)Foxp3(+) T(reg) cells. Functional deletion of tumor-infiltrating T(reg) cells could enhance tumor-specific immunotherapy.
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PMID:Compromised lymphocytes infiltrate hepatocellular carcinoma: the role of T-regulatory cells. 1578 65

Wild-type (WT) sequence p53 peptides are attractive candidates for broadly applicable cancer vaccines. The aim of this study was to evaluate the potential of a WT p53-based immunotherapeutic approach for patients with hepatocellular carcinoma (HCC). Circulating CD8+ T cells specific for WT p53(149-157) and WT p53(264-272) HLA-A*0201 restricted epitopes were directly identified in the peripheral blood by the use of peptide/HLA-A2.1 tetramers in 24 HCC patients. Cytotoxic T lymphocyte (CTL) activity after WT p53 peptide-specific stimulation was assessed by analysis of granzyme B and interferon-gamma mRNA transcription, using a quantitative real-time polymerase chain reaction assay. Tumor immunophenotyping was performed to evaluate the p53 status, the expression of major histocompatibility complex (MHC) and costimulatory molecules in freshly isolated tumor cells. HCC patients exhibited significantly higher frequencies of WT p53-specific memory CD8+ T cells and stronger WT p53-specific CTL activity, when compared with healthy controls. Increased frequencies of p53-specific CD8+ T cells and their activity correlated with selective HLA-A2 allele loss and reduced costimulatory molecule expression of tumor cells. Moreover, augmented numbers of p53-specific T cells coincided with high MHC class II expression in tumor cells but were inversely related to the T status of the tumor node metastasis staging system. Our results indicate the existence of natural immunosurveillance and tumor immune evasion, involving a T cell response against WT p53 tumor antigen in patients with HCC. These findings may have important implications for the future development of cancer vaccines.
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PMID:Increased frequencies of CD8+ T lymphocytes recognizing wild-type p53-derived epitopes in peripheral blood correlate with presence of epitope loss tumor variants in patients with hepatocellular carcinoma. 1699 81

Dysfunction of the host immune system in cancer patients can be due to a number of factors, including suppression of tumor-associated antigen reactive lymphocytes by CD4(+)CD25(+) regulatory T (Treg) cells. Several studies suggest that Tregs are elevated in cancer patients and that depletion of Tregs may enhance the antitumor immunity of host, but the pathogenic and mechanistic relationship between cancer and Tregs is still unclear. In this report, we show that Tregs are increased in peripheral blood mononuclear cells (PBMCs) from hepatocellular carcinoma (HCC) patients and positively correlate with tumor burden. When PBMCs are co-cultured with human hepatoma cell lines Huh7, HepG2, and Hclone5, CD4(+)CD25(+)-T cell populations increase in frequency and undergo phenotypic and functional changes. CD45RA, CD45RO, CD69, CD62L, GITR, CTLA-4, Ki67, granzyme A, granzyme B, and FOXP3 expression were upregulated in CD4(+)CD25(+) cells after in vitro exposure to HCC cell lines. CD4(+)CD25(+) T cells from PBMCs that were co-cultured with Huh7 cells also have higher suppressor ability compared to that of the CD4(+)CD25(+) T cells from control PBMC. Huh7 culture supernatants appear to promote CD4(+)CD25(+) T-cell proliferation and inhibit CD4(+)CD25(-) T-cell proliferation. In conclusion, these results strongly suggest that tumor-related factors not only induce and expand CD4(+)CD25(+) cells, but also enhance their suppressor ability.
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PMID:Hepatocellular carcinoma cell supernatants increase expansion and function of CD4(+)CD25(+) regulatory T cells. 1737 88

The MAGE-A3 protein, one of the promising tumor antigens for immunotherapy, is highly expressed in human hepatocellular carcinoma (HCC). In this study, we estimated the specific CD8(+) T cell immune response to MAGE-A3 p271-279 peptide (M3(271)) in the peripheral blood of HCC patients without antigen vaccination in order to evaluate its immunotherapeutic potential in these patients. After expansion in vitro, the functional IFN-gamma producing M3(271) specific CD8(+) T cells were detected in 30.8% (8/26) of HLA-A2(+)MAGE-A3(+) HCC patients. The effector CD8(+ )T cells could release cytotoxic molecules of granzyme B and perforin after restimulation with natural HLA-A2(+)MAGE-A3(+) HCC cell lines in the samples tested. The functional supertype of HLA-A2 in the presentation of HLA-A*0201 restricted M3(271) peptide has been identified in the Chinese HCC patients of Han ethnicity, that widely expanded the applicability of this tumor peptide vaccine in Chinese HCC patients. Thus, the functionally detectable pre-existence of M3(271)-specific CD8(+) T cells in HCC patients makes M3(271) a potential target for immunotherapy in these patients. The responsive CD8(+ )T cells to both NY-ESO-1 and MAGE-A3 antigens provide a rationale for the application of a bivalent vaccine in HCC patients with tumors expressing both antigens.
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PMID:Specific CD8(+ )T cell responses to HLA-A2 restricted MAGE-A3 p271-279 peptide in hepatocellular carcinoma patients without vaccination. 1752 59

Hepatocellular carcinoma (HCC) is one of the most common malignant tumours in the world, especially in Guangxi, China. The causes and mechanism of its tumourigenesis and development have not been completely clarified Some studies revealed that the hepatic local cellular immune function was one of the factors. In the present study, the local micro-environmental immune status was explored by investigating the number, distribution and function of CD3, CD57, CD20, CD68, and granzyme B (GrB) positive cells in 60 patients with HCC and 62 patients with liver cirrhosis (LC) and its relationship with the prognosis of the patients. The results showed that the number of T and B lymphocytes and natural killer (NK) cells in the liver of HCC patients was significantly higher than that in the LC and normal controls; while the number of macrophages (Mphi) was significantly lower The number of Mphi in the tissues decreased successively with the decrease of HCC differentiation; GrB-expressing cells in the liver predominantly consisted of CD57 positive cells. The number of NK cells, B lymphocytes and GrB-expressing cells in the cancerous tissues of stage I and II was significantly higher than that of stages III and IV. The number of T lymphocytes, NK cells, Mphi, and GrB-expressing lymphocytes in HCC cases without metastasis in 15 months was significantly higher than in the metastatic counterparts. The number of T and B lymphocytes, NK cells, and GrB-expressing cells decreased in patients with the progression of the HCC. These results suggest that the number of T and B lymphocytes, NK cells, Mphi and GrB-positive lymphocytes might be important markers in the estimation of hepatic local immune status and be useful factors for predicting the prognosis of HCC patients.
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PMID:Hepatic local micro-environmental immune status in hepatocellular carcinoma and cirrhotic tissues. 1769 Dec 35

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