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ABSTRACT: Tim-3, a member of the novel Tim (T cell immunoglobulin and mucin domain) family, has been reported to negatively regulate the immune responses against viral infection and had implications for autoimmune disease. However, the nature and role of Tim-3(+) CD4 T cells in human tumors remain largely unknown. In the present study, we characterized Tim-3(+) CD4 T cells in 100 specimens from human hepatocellular, cervical, colorectal and ovarian carcinoma patients. Compared with peripheral blood and nontumor-infiltrating lymphocytes, the lymphocytes isolated from the corresponding tumor tissues of hepatocellular, cervical, colorectal and ovarian carcinoma patients contained significantly greater proportion of Tim-3(+) CD4 T cells. The majority of tumor-derived Tim-3(+) CD4 T cells exhibited an impaired capacity to produce IFN-γ and IL-2, but expressed higher levels of CD25, Foxp3, CTLA-4 and GITR than their Tim-3(-) CD4 T cell counterparts. In contrast, most Tim-3(+) CD4 T cells isolated from the paired nontumor tissues and peripheral blood did not express these molecules. Moreover, tumor-derived Tim-3(+) CD4 T cells, but not tumor-derived Tim-3(-) CD4 T cells, significantly suppressed the proliferation of autologous CD8(+) T cells in vitro. Notably, multi-color immunofluorescence and confocal microscopy demonstrated that Tim-3(+)Foxp3(+)CD4(+) cells were preferentially distributed in the tumor nest rather than the peritumoral stroma of hepatocellular carcinoma. Together, our data indicate that Tim-3-expressing CD4 T cells in human tumors could represent the functional regulatory T cells which contribute to the formation of the immune-suppressive tumor micromilieu.
PLoS ONE 01/2013; 8(3):e58006. · 4.09 Impact Factor
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ABSTRACT: Transarterial chemoembolization (TACE) has therapeutic effects in patients with unresectable hepatocellular carcinoma (HCC), but its impact on the cellular immune response during disease progression is largely unknown. Here we conducted a prospective study to evaluate the effect of TACE on immune status and to identify prognostic immune markers governing treatment success. In this study, 51 stage III HCC patients, 28 stage I HCC patients (TNM classification) and 20 healthy donors were enrolled. Flow cytometry and cytometric bead array were used to evaluate the circulating immune cell subsets, including CD4(+) T cells (Th1, Th17 and Treg cells), CD8(+) T cells, NK cells, and NKT cells, and plasma cytokines before TACE and 30 days after TACE. Interestingly, among those immune parameters, the frequency of circulating Th17 cells was higher in stage III HCC patients than in stage I HCC patients (P = 0.015) and healthy donors (P<0.001). Moreover, an increased frequency of circulating Th17 cells was observed 30 days after TACE (Th17 D30 ) compared with the baseline level (P = 0.036). Kaplan-Meier analysis demonstrated that Th17 D30 was positively associated with overall survival (OS; P = 0.007) and time to progression (TTP; P = 0.009). Multivariate Cox analysis revealed that Th17 D30 was an independent prognostic factor for OS (HR = 0.317, P = 0.032) and TTP (HR = 0.304, P = 0.010). These results provide a potential prognostic marker for stage III HCC patients undergoing TACE and may be useful for identifying patients who can benefit from adjuvant immunotherapies.
PLoS ONE 01/2013; 8(4):e60444. · 4.09 Impact Factor
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ABSTRACT: Defects in NK cell functions are necessary for tumor immune escape, but their underlying regulatory mechanisms in human cancers remain largely unknown. Here we showed, in detailed studies of NK cells in 294 untreated patients with hepatocellular carcinoma (HCC), that accumulation of functional NK cells in HCC tissues could predict improved survival of patients. However, in patients with advanced stage HCC, NK cells were significantly decreased in number with impaired TNF-α and IFN-γ production. High infiltration of peritumoral stroma monocytes/macrophages was positively correlated with impaired functional activities of NK cells in intratumoral areas. Further kinetic experiments revealed that soon after exposure to tumor-derived monocytes, NK cells underwent a rapid, transient activation, but then they became exhausted, and eventually died. The monocytes from HCC tissues, but not from nontumoral liver, strongly express CD48 proteins; and such monocyte-induced NK cell dysfunction was markedly attenuated by blocking CD48 receptor 2B4 on NK cells, but not by blockade of NKG2D and NKp30. Conclusion: These data reveal that human NK cells are regulated by a fine-tuned collaborative action between different types of immune cells, which may reflect a novel immune-escape mechanism by which tumors dynamically regulate their functions at distinct tumor microenvironments. (HEPATOLOGY 2012.).
Hepatology 12/2012; · 11.66 Impact Factor
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ABSTRACT: Human tumor tissues can often be anatomically classified into areas of cancer nest, invading edge, and peritumoral stroma, each with distinct compositions and functional properties. Macrophages (Mφ) constitute a major component of the leukocyte infiltrate in tumors. These cells are derived from circulating monocytes, and in response to environmental signals, they exhibit distinct phenotypes with diverse functions. Soluble factors derived from cancer cells can alter the normal developmental process of Mφ that is intended to trigger transient early activation of monocytes in the peritumoral region, which in turn induces formation of suppressive Mφ in cancer nests. The activated monocytes in the peritumoral region attenuated the T-cell response by expressing B7-H1, and were superior to the suppressive tumor Mφ in inducing Th17 expansion, and thus repurpose the inflammatory response away from anti-tumor immunity (the sword) and towards tissue remodeling and proangiogenic pathways (a plowshare). In contrast, the suppressive Mφ can induce the production of Tregs in cancer nest. Accordingly, angiogenesis was most active at the invading edge, which was situated close to the peritumoral stroma with activated Mφ and the density of these activated monocytes is selectively associated with vascular invasion and metastasis in patients with hepatocellular carcinoma. These data reveal an intriguing mechanism in which human Th17 cells are generated and regulated by a fine-tuned collaborative action between different types of immune cells in distinct tumor microenvironments. These results give important new insights into the distinct role of macrophages in human tumor progression which would be helpful for the rational design of novel immune-based anticancer therapies.
Cancer Microenvironment 06/2012; 5(3):195-201.
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Jing Xu,
Tong Ding,
Qi He,
Xing-Juan Yu,
Wen-Chao Wu,
Wei-Hua Jia,
Jing-Ping Yun,
Ying Zhang,
Ming Shi,
Chun-Kui Shao,
Wei-Dong Pan,
Xiao-Yu Yin,
Jun Min,
Shi-Mei Zhuang, Limin Zheng
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ABSTRACT: To develop an in situ molecular signature to predict postsurgical recurrence in hepatocellular carcinoma (HCC) patients.
Immunohistochemistry was performed using tissue microarrays containing both tumoral and peri-tumoral regions of the advancing tumor edge from 336 HCC patients (289 were positive for hepatitis B virus) who underwent curative resection. Forty-nine variables were analyzed in the training set (n=151) using support vector machine and stepwise algorithms to develop a classifier to predict recurrence within 1 year, which was mainly caused by invasion or metastasis from the primary tumors. The classifier was further validated in an independent cohort of 185 patients (71 internal and 114 external).
The final signature was composed of eight IHC features: CD80(T), B7-DC(T), HLA-DR(P), FasL(P), Bcl-2(T), Ki-67(T), cyclin D1(T), and CK19(T). In the independent test set, this classifier reliably predicted recurrence within 1 year (sensitivity, 69.1%; specificity, 65.0%) with an odds ratio of 4.149 (95% CI, 2.189-7.864). Based on a multivariate logistic model, the in situ molecular signature provided significant predictive power independent of tumor number, tumor size, vascular invasion and BCLC classification (p=0.001). The highest potential clinical impact of the classifier was observed in early-stage (BCLC classification 0-A) patients (p<0.0001), and the classifier was also predictive of the time-to-recurrence and overall survival (both p<0.0001).
This in situ molecular classifier could provide a novel approach to identify patients who are at greatest risk for postsurgical recurrence of HCC and may benefit from intensive clinical follow-up or chemopreventive strategies.
Journal of Hepatology 04/2012; 57(2):313-21. · 9.26 Impact Factor
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03/2012; , ISBN: 978-953-51-0439-1
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ABSTRACT: Substantial evidence indicates that immune activation at stroma can be rerouted in a tumor-promoting direction. CD69 is an immunoregulatory molecule expressed by early-activated leukocytes at sites of chronic inflammation, and CD69(+) T cells have been found to promote human tumor progression. In this study, we showed that, upon encountering autologous CD69(+) T cells, tumor macrophages (MΦs) acquired the ability to produce much greater amounts of IDO protein in cancer nests. The T cells isolated from the hepatocellular carcinoma tissues expressed significantly more CD69 molecules than did those on paired circulating and nontumor-infiltrating T cells; these tumor-derived CD69(+) T cells could induce considerable IDO in monocytes. Interestingly, the tumor-associated monocytes/MΦs isolated from hepatocellular carcinoma tissues or generated by in vitro culture effectively activated circulating T cells to express CD69. IL-12 derived from tumor MΦs was required for early T cell activation and subsequent IDO expression. Moreover, we found that conditioned medium from IDO(+) MΦs effectively suppressed T cell responses in vitro, an effect that could be reversed by adding extrinsic IDO substrate tryptophan or by pretreating MΦs with an IDO inhibitor 1-methyl-DL-tryptophan. These data revealed a fine-tuned collaborative action between different types of immune cells to counteract T cell responses in tumor microenvironment. Such an active induction of immune tolerance should be considered for the rational design of effective immune-based anticancer therapies.
The Journal of Immunology 12/2011; 188(3):1117-24. · 5.79 Impact Factor
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Dong Li,
Xingguang Liu,
Li Lin,
Jin Hou,
Nan Li,
Chunmei Wang,
Pin Wang,
Qian Zhang,
Peng Zhang,
Weiping Zhou,
Zhengxin Wang,
Guoshan Ding,
Shi-Mei Zhuang, Limin Zheng,
Wenzhao Tao,
Xuetao Cao
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ABSTRACT: In our in-depth analysis carried out by the Illumina Solexa massive parallel signature sequencing, microRNA-99a (miR-99a)
was found to be the sixth abundant microRNA in the miRNome of normal human liver but was markedly down-regulated in hepatocellular
carcinoma (HCC). Compelling evidence has suggested the important roles of microRNAs in HCC development. However, the biological
function of miR-99a deregulation in HCC remains unknown. In this study, we found that miR-99a was remarkably decreased in
HCC tissues and cell lines. Importantly, lower miR-99a expression in HCC tissues significantly correlated with shorter survival
of HCC patients, and miR-99a was identified to be an independent predictor for the prognosis of HCC patients. Furthermore,
restoration of miR-99a dramatically suppressed HCC cell growth in vitro by inducing the G1 phase cell cycle arrest. Intratumoral injection of cholesterol-conjugated miR-99a mimics significantly inhibited tumor growth
and reduced the α-fetoprotein level in HCC-bearing nude mice. Insulin-like growth factor 1 receptor (IGF-1R) and mammalian
target of rapamycin (mTOR) were further characterized as the direct targets of miR-99a. Furthermore, protein levels of IGF-1R
and mTOR were found to be inversely correlated with miR-99a expression in HCC tissues. miR-99a mimics inhibited IGF-1R and
mTOR pathways and subsequently suppressed expression of cell cycle-related proteins, including cyclin D1 in HCC cells. Conclusively,
miR-99a expression was frequently down-regulated in HCC tissues and correlates with the prognosis of HCC patients, thus proposing
miR-99a as a prospective prognosis predictor of HCC. miR-99a suppresses HCC growth by inducing cell cycle arrest, suggesting
miR-99a as potential tumor suppressor for HCC therapeutics.
Journal of Biological Chemistry 10/2011; 286(42):36677-36685. · 4.77 Impact Factor
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Dong Li,
Xingguang Liu,
Li Lin,
Jin Hou,
Nan Li,
Chunmei Wang,
Pin Wang,
Qian Zhang,
Peng Zhang,
Weiping Zhou,
Zhengxin Wang,
Guoshan Ding,
Shi-Mei Zhuang, Limin Zheng,
Wenzhao Tao,
Xuetao Cao
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ABSTRACT: In our in-depth analysis carried out by the Illumina Solexa massive parallel signature sequencing, microRNA-99a (miR-99a) was found to be the sixth abundant microRNA in the miRNome of normal human liver but was markedly down-regulated in hepatocellular carcinoma (HCC). Compelling evidence has suggested the important roles of microRNAs in HCC development. However, the biological function of miR-99a deregulation in HCC remains unknown. In this study, we found that miR-99a was remarkably decreased in HCC tissues and cell lines. Importantly, lower miR-99a expression in HCC tissues significantly correlated with shorter survival of HCC patients, and miR-99a was identified to be an independent predictor for the prognosis of HCC patients. Furthermore, restoration of miR-99a dramatically suppressed HCC cell growth in vitro by inducing the G(1) phase cell cycle arrest. Intratumoral injection of cholesterol-conjugated miR-99a mimics significantly inhibited tumor growth and reduced the α-fetoprotein level in HCC-bearing nude mice. Insulin-like growth factor 1 receptor (IGF-1R) and mammalian target of rapamycin (mTOR) were further characterized as the direct targets of miR-99a. Furthermore, protein levels of IGF-1R and mTOR were found to be inversely correlated with miR-99a expression in HCC tissues. miR-99a mimics inhibited IGF-1R and mTOR pathways and subsequently suppressed expression of cell cycle-related proteins, including cyclin D1 in HCC cells. Conclusively, miR-99a expression was frequently down-regulated in HCC tissues and correlates with the prognosis of HCC patients, thus proposing miR-99a as a prospective prognosis predictor of HCC. miR-99a suppresses HCC growth by inducing cell cycle arrest, suggesting miR-99a as potential tumor suppressor for HCC therapeutics.
Journal of Biological Chemistry 08/2011; 286(42):36677-85. · 4.77 Impact Factor
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ABSTRACT: A high prevalence of serum IL-6 has been associated with the pathogenesis of hepatocellular carcinoma (HCC) in both animals and humans. However, it is not clear how the levels of serum IL-6 influence the prognosis of HCC patients. This study was carried out in order to attempt to answer this question.
A total of 156 adults were selected and categorized into four groups: healthy subjects (n=18), those with tumor recurrence (n=26), those initially diagnosed with HCC (n=32), and those with HCC (n=80) who received curative resection between 2002 and 2004 with five years of follow-up. Serum IL-6 levels were determined in all subjects by the same ELISA method.
IL-6 was found in high levels in the serum of patients initially diagnosed with HCC (8.47±5.92, p<0.0001) and in patients with HCC and tumor recurrence (12±31.90, p=0.001) compared with healthy subjects (0.89±1.51). This includes all patients who received therapy between 2007 and 2008. The levels of serum IL-6 were positively correlated with tumor size (p=0.002) in the HCC patients who received curative resection between 2002 and 2004 with five years of follow-up.
High levels of serum IL-6 correlated positively with tumor size and with poor prognosis in HCC patients.
Hepato-gastroenterology 07/2011; 58(110-111):1687-93. · 0.66 Impact Factor
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ABSTRACT: Distinct morphologic features of microvascular endothelium exist in tumor tissues. The objective of this study was to investigate the prognostic value of endothelium-coated tumor clusters (ECTCs) in hepatocellular carcinoma (HCC).
ECTCs were evaluated by immunohistochemical staining for cluster of differentiation 34 (CD34) (a cell surface glycoprotein which is expressed specifically on tumor microvascular endothelium in HCC) in 239 specimens from patients with primary HCC. Overall survival (OS) and time to recurrence (TTR) were determined using Kaplan-Meier analysis and a Cox proportional hazards regression model. Levels of terminal deoxynucleotide transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) staining, and Ki-67 expression, and E-cadherin expression were assessed to determine tumor apoptosis, proliferation, and invasiveness, respectively.
The presence of ECTCs was associated with a poor prognosis in all patients and in patient subgroups stratified by tumor size, TNM classification, and Barcelona Clinic Liver Cancer stage and tumor invasiveness. In a multivariate Cox proportional hazards analysis, the presence of ECTCs emerged as an independent prognostic indicator of both poor OS (P = .001; hazard ratio, 1.949) and shorter TTR (P < .001; hazard ratio, 2.085). Furthermore, the presence of ECTCs was associated with micrometastatic endothelium-coated emboli (P < .001; chi-square test) and early relapse after resection (P < .001; chi-square test). In addition, patients who had endothelium-coated emboli, in which tumor cells displayed high proliferation and low apoptosis, had poor OS and shorter TTR.
The current results suggested that the presence of ECTCs was an efficient, simple, and convenient predictor of a poor prognosis in patients with HCC that potentially may serve as a novel target for the prevention and treatment of HCC metastasis.
Cancer 04/2011; 117(21):4878-89. · 4.77 Impact Factor
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ABSTRACT: Theoretical studies of the potential energy surface and bound states were performed for the N(2)O dimer. A four-dimensional intermolecular potential energy surface (PES) was constructed at the CCSD(T) level with aug-cc-pVTZ basis set supplemented with bond functions. Three co-planar local minima were found on this surface. They correspond to a nonpolar isomer with slipped-antiparallel planar structure and two equivalent polar isomers with slipped-parallel planar structures. The nonpolar isomer is energetically more stable than the polar ones by 162 cm(-1). To assign the fundamental vibrational frequencies for both isomers, more than 150 vibrational bound states were calculated based on this PES. The orientation of the nodal surface of the wave functions plays an important role in the assignment of disrotation and conrotation vibrational modes. The calculated vibrational frequencies are in good agreement with the available experimental data. We have also found a quantum tunneling effect between the two equivalent polar structures in the higher vibrational excited states. Rotational transition frequencies of the polar structure were also calculated. The accuracy of the PES is validated by the good agreement between theoretical and experimental results for the transition frequencies and spectroscopic parameters.
The Journal of chemical physics 02/2011; 134(5):054311. · 3.09 Impact Factor
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Jin Hou,
Li Lin,
Weiping Zhou,
Zhengxin Wang,
Guoshan Ding,
Qiongzhu Dong,
Lunxiu Qin,
Xiaobing Wu,
Yuanyuan Zheng,
Yun Yang,
Wei Tian,
Qian Zhang,
Chunmei Wang,
Qinghua Zhang,
Shi-Mei Zhuang, Limin Zheng,
Anmin Liang,
Wenzhao Tao,
Xuetao Cao
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ABSTRACT: The full scale of human miRNome in specific cell or tissue, especially in cancers, remains to be determined. An in-depth analysis of miRNomes in human normal liver, hepatitis liver, and hepatocellular carcinoma (HCC) was carried out in this study. We found nine miRNAs accounted for ∼88.2% of the miRNome in human liver. The third most highly expressed miR-199a/b-3p is consistently decreased in HCC, and its decrement significantly correlates with poor survival of HCC patients. Moreover, miR-199a/b-3p can target tumor-promoting PAK4 to suppress HCC growth through inhibiting PAK4/Raf/MEK/ERK pathway both in vitro and in vivo. Our study provides miRNomes of human liver and HCC and contributes to better understanding of the important deregulated miRNAs in HCC and liver diseases.
Cancer cell 02/2011; 19(2):232-43. · 25.29 Impact Factor
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ABSTRACT: Macrophages (Mφ) and regulatory T cells (Tregs) are the major components of the inflammatory infiltrate in virtually all tumors. The objective of this study was to investigate the prognostic significance of Mφ and Tregs infiltration in advanced gastric cancer after radical resection.
CD68(+) Mφ and FOXP3(+) Tregs were assessed by immunohistochemistry in tissues from 107 patients with surgically advanced gastric cancer. The microlocalization of Mφ and Tregs cells with respect to the development of gastric cancer were given special concern. Prognostic value of normal, peritumoral, and intratumoral Mφ and Tregs densities was evaluated by Kaplan-Meier analysis and Cox regression.
The results showed that the presence of intratumoral CD68(+) Mφ was an independent prognostic factor for overall survival (OS) (P = 0.02). Moreover, the combination of high numbers of intratumoral CD68(+) Mφ and FOXP3(+) Tregs was associated with improved survival (P = 0.041). Five-year OS rate was only 27% for patients with low intratumoral Mφ and intratumoral Tregs compared with 62% for patients with high intratumoral Mφ and intratumoral Tregs. In addition, advanced intestinal-type gastric cancers were more likely to have fewer infiltrating Mφ than diffuse-type cancers (P = 0.024).
Association of intratumoral Mφ and Tregs is a promising independent predictor for survival in advanced gastric cancer. The results suggested that a combination of concomitant stimulation of intratumoral Mφ and Tregs may be an effective strategy for treatment of patients with advanced gastric cancer after radical resection.
Annals of Surgical Oncology 02/2011; 18(9):2585-93. · 4.17 Impact Factor
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ABSTRACT: Substantial evidence indicates that inflammation is a critical component of tumor progression. Hepatocellular carcinoma (HCC) is usually derived from inflamed cirrhotic liver with extensive leukocyte infiltration. Neutrophils are the common inflammatory infiltrate in tumors, but their nature and regulation in human cancers remain elusive.
A total of 238 HCC patients were enrolled randomly. Immunohistochemistry and SuperArray Real-Time PCR were used to analyze the distribution and clinical relevance of neutrophils in different microanatomical areas. The regulation and function of neutrophils were assessed by both in vitro and in vivo studies.
Neutrophils were enriched predominantly in peritumoral stroma of HCC tissues and their levels could serve as a powerful predictor for poor survival in HCC patients. Proinflammatory IL-17 is a critical mediator of the recruitment of neutrophils into peritumoral stroma of HCC tissues by epithelial cell-derived CXC chemokines. The accumulated peritumoral neutrophils were the major source of matrix metalloproteinase-9 in HCC tissues; this secreted protein stimulated proangiogenic activity in hepatoma cells. Accordingly, high infiltration of peritumoral neutrophils was positively correlated with angiogenesis progression at tumor-invading edge of HCC patients. Furthermore, we found that selective depletion of neutrophils effectively inhibited tumor angiogenesis and growth, in vivo.
These data provide direct evidence supporting the critical role of neutrophils in human tumor progression and reveal a fine-tuned collaborative action between cancer cells and immune cells in distinct tumor milieu, which reroutes the inflammatory response into a tumor-promoting direction.
Journal of Hepatology 11/2010; 54(5):948-55. · 9.26 Impact Factor
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ABSTRACT: With the development of network technology, the future network is an open and reconfigurable network architecture whose functions are reorganizational, capabilities are programmable and managements are reconfigurable. According to the feature of the future network that is application-oriented reconfigurable, this paper proposed a design of integrated network management system. The system is based on the open and reconfigurable network. The characteristic of the system is application-oriented and reconstructed. The paper also created a prototype system, tested and verified the prototype system by using the example of reconfigure IPSec VPN services.
Advanced Computer Theory and Engineering (ICACTE), 2010 3rd International Conference on; 09/2010
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ABSTRACT: The proinflammatory IL-17-producing CD8(+) T cells (Tc17 cells) have recently been detected in tumors, but the nature and regulation of these cells in human tumors are presently unknown. We have recently found that IL-17(+) cells are accumulated in human hepatocellular carcinomas (HCC), where they promote disease progression by fostering angiogenesis. In this study, we showed that Tc17 cells constitute a remarkable portion of IL-17-producing cells in human HCC. Although most circulating Tc17 cells were negative for IFN-gamma, >80% of Tc17 cells in HCC tissues were positive for IFN-gamma, and they were enriched predominantly in invading tumor edge. Most CD68(+) cells located in invading tumor edge exhibited an activated phenotype and, accordingly, the activated monocytes isolated from HCC tissues were significantly superior to those isolated from nontumor tissues in inducing expansion of Tc17 cells in vitro with phenotypic features similar to those isolated from tumors. Compared with IL-17(-)IFN-gamma(+)CD8(+) cells, these IFN-gamma(+)Tc17 cells have significantly higher expression of proinflammatory cytokines (IL-2, IL-22, and TNF-alpha), but reduced expression of granzyme B and perforin. Moreover, we found that tumor-activated monocytes secreted a set of key cytokines (IL-1beta, IL-6, and IL-23) to trigger the proliferation of Tc17 cells. These data reveal an intriguing mechanism in which human Tc17 cells are generated by a fine-tuned collaborative action between different types of immune cells in distinct tumor microenvironments.
The Journal of Immunology 08/2010; 185(3):1544-9. · 5.79 Impact Factor
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ABSTRACT: Density functional theory calculations have been performed to study the geometrical and electronic properties of endohedral metallofullerene Tm@C(82) isomers. Three energetically favorable isomers (with C(s), C(2) and C(2v) symmetry, respectively) are identified which are consistent with the nuclear magnetic resonance (NMR) observations. The simulated ultraviolet photoelectron spectra (UPS) based on the three structures agree well with the measurements. Particularly, the parent cage of the experimentally observed Tm@C(82) isomer with C(s) symmetry is newly assigned, which matches the experiments better than early assignments. In addition, strong interaction between an endohedral Tm atom and the C(82) cage is discussed and is thought to be responsible for the dramatic change in the relative stability of C(82) isomers when Tm is encapsulated.
Journal of Physics Condensed Matter 06/2010; 22(23):235301. · 2.55 Impact Factor
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ABSTRACT: Macrophages (Mphi) are prominent components of solid tumors and exhibit distinct phenotypes in different microenvironments. We have recently found that tumors can alter the normal developmental process of Mphi to trigger transient activation of monocytes, but the underlying regulatory mechanisms are incompletely understood. Here, we showed that the protein expression of transcription factor C/EBPbeta was markedly elevated in tumor-associated Mphi both in vitro and human tumors in situ. The expression of C/EBP protein correlated with cytokine production in tumor-activated monocytes. Moreover, we found that C/EBPbeta expression was regulated at the post-transcriptional level and correlated with sustained reduction of microRNA-155 (miR-155) in tumor-activated monocytes. Bioinformatic analysis revealed that C/EBPbeta is a potential target of miR-155 and luciferase assay confirmed that C/EBPbeta translation is suppressed by miR-155 through interaction with the 3'UTR of C/EBPbeta mRNA. Further analysis showed that induction of miR-155 suppressed C/EBPbeta protein expression as well as cytokine production in tumor-activated monocytes, an effect which could be mimicked by silencing of C/EBPbeta. These results indicate that tumor environment causes a sustained reduction of miR-155 in monocytes/Mphi, which in turn regulates the functional activities of monocytes/Mphi by releasing the translational inhibition of transcription factor C/EBPbeta.
Cellular & molecular immunology 10/2009; 6(5):343-52. · 2.99 Impact Factor
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ABSTRACT: Modified vaccinia virus Ankara (MVA) has attracted significant attention as a safe, promising vector for immunotherapy. However, the precise effects of MVA infection on immune responses in humans remain largely unknown. We constructed recombinant MVA (rMVA) encoding both a human tumor-associated antigen (survivin) and the proinflammatory cytokine interleukin (IL)-2 and investigated their effects on human monocyte-derived dendritic cells (DCs). The results showed that infection with rMVA slightly impaired the upregulation of CD83 and reduced the production of IL-10 in DCs after lipopolysaccharide stimulation. However, rMVA-infected DCs were still able to express high levels of target genes and the costimulatory molecules CD80 and CD86 and to produce significant amounts of the proinflammatory cytokine tumor necrosis factor alpha. Moreover, rMVA-infected DCs exhibited a greater capacity than uninfected cells to stimulate T-cell proliferation and to reverse MVA-induced apoptosis in syngeneic T cells. Coculture of lymphocytes with rMVA-infected DCs significantly increased cytotoxic potential and interferon gamma production by cytotoxic T cells. These findings suggest that rMVA encoding survivin and IL-2 can effectively stimulate the activation of human DCs and overcome defects such as impairment of DC maturation and apoptosis of lymphocytes that are caused by vector alone. Thus, this study may provide a rational basis for further optimization of MVA vector.
Human gene therapy 09/2009; 21(1):98-108. · 4.20 Impact Factor
