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ABSTRACT: Abstract Background: Cytokine-induced killer (CIK) cells have demonstrated antitumor effects in vitro and in vivo. The purpose of this study was to evaluate the effect of CIK cell treatment as an adjuvant immunotherapy on the prognosis of gastric carcinoma in patients after surgery. Methods: The patients with stage II-III gastric carcinoma after gastrectomy, including 53 patients receiving autologous CIK cell treatment combined with chemotherapy (CIK group) and 112 patients in the corresponding period receiving chemotherapy alone (control group), were retrospectively studied. The patients in the CIK group were matched to those in the control group regarding the sex and age of patients, tumor site, histological type, pathological grade, tumor size, clinical stage, and chemotherapy plan. Progression-free survival (PFS) and overall survival (OS) were evaluated. Results: The 5-year OS rate in the CIK group was significantly improved compared to that in the control group (56.6% vs. 26.8%, p=0.014). The 5-year PFS rate in the CIK group was also significantly improved compared to that in the control group (49.1% vs. 24.1%, p=0.026). The median PFS (36.0 months) and OS (96.0 months) in the CIK group were significantly prolonged than those in the control group (23.0 months for median PFS and 32.0 months for median OS, p=0.028 and p=0.003). No serious side effect was observed in the CIK group. Conclusions: This study suggests that immunotherapy with CIK cells may serve as an adjuvant treatment to prolong the survival of patients with stage II-III gastric carcinoma.
Cancer Biotherapy & Radiopharmaceuticals 03/2013; · 1.44 Impact Factor
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ABSTRACT: Abstract MicroRNAs (miRNAs) are a class of endogenous small noncoding regulatory RNAs, which are new regulators of gene expression. They interfere with multiple biological processes involved in tumorigenesis such as cell proliferation, cell cycle, apoptosis, angiogenesis, invasion, and metastasis. A large body of evidence shows that the aberrant expression of miRNAs in cancer patients provides numerous underlying merits as diagnostic, clinical pathological, prognostic markers, and as promising therapeutic targets of lung cancer, providing an insight into the clinical application for lung cancer. Here, we focus on specific miRNAs as biomarkers in lung cancer and briefly introduce the biological function and modification of miRNAs.
Cancer Biotherapy & Radiopharmaceuticals 03/2013; · 1.44 Impact Factor
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ABSTRACT: Myeloid-derived suppressor cells (MDSCs) represent heterogeneous immunosuppressive cells in multiple cancer types and display potent immunosuppressive activity on T cells. We have shown the increased expression of IDO in breast cancer. Because IDO plays a pivotal role in immune tolerance via suppressing T cell function, the aim of this study was to investigate the expression of IDO in MDSCs in breast cancer and its role in MDSC-mediated inhibition of immune surveillance. The proportion of MDSCs with the phenotype of CD45(+)CD13(+)CD33(+)CD14(-)CD15(-) significantly increased in primary cancer tissues and patients' peripheral blood. IDO expression was significantly upregulated in MDSCs isolated from fresh breast cancer tissues (fresh MDSCs [fMDSCs]), which correlated with increased infiltration of Foxp3(+) regulatory T cells in tumors and lymph node metastasis in patients. fMDSCs inhibited IL-2 and anti-CD3/CD28 mAb-induced T cell amplification and Th1 polarization but stimulated apoptosis in T cells in an IDO-dependent manner. CD33(+) progenitors isolated from healthy donors' umbilical cord blood were cocultured with breast cancer cell line MDA-MB-231 cells to induce MDSCs. IDO expression was upregulated in induced MDSCs, which required phosphorylation of STAT3, but not STAT1. IDO was required for induced MDSCs' immunosuppressive activity on T cells, which was blocked by IDO inhibitor 1-methyl-l-tryptophan or STAT3 antagonist JSI-124. Consistently, increased STAT3 phosphorylation level was found in fMDSCs. Together, our findings suggest that STAT3-dependent IDO expression mediates immunosuppressive effects of MDSCs in breast cancer. Thus, inhibition of MDSC-induced T cell suppression by blocking IDO may represent a previously unrecognized mechanism underlying immunotherapy for breast cancer.
The Journal of Immunology 02/2013; · 5.79 Impact Factor
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ABSTRACT: BACKGROUND: The relationship between body mass index (BMI) and long-term outcome in gastric cancer patients following radical gastrectomy continues to be debated. We investigated the association between BMI, clinicopathological features, and prognosis in Chinese gastric carcinoma patients. METHODS: A retrospective consecutive cohort study was performed on 1,296 patients who underwent gastrectomy with curative intent at the Tianjin Cancer Institute Hospital between 1999 and 2004. The clinicopathological characteristics, overall 5-year survival rate (OS), and preoperative and six-month postoperative BMIs of both overweight (BMI ≥25 kg/m(2); H-BMI; n = 364) and non-overweight (BMI <25 kg/m(2); N-BMI; n = 932) patients were compared. RESULTS: Among these patients, 364 (28.1 %) were overweight. The OS was significantly higher in the H-BMI than N-BMI group (33.2 vs. 24.1 %, respectively; p < 0.001). Preoperative and six-month postoperative BMIs were 27.1 ± 2.0 and 24.8 ± 2.0 kg/m(2), respectively, in the H-BMI group (p < 0.001), whereas they were 21.7 ± 2.2 and 20.7 ± 2.2 kg/m(2), respectively, in the N-BMI group (p = 0.007). There was significantly better differentiation (p = 0.034), less distant metastases (p = 0.006), and a lower metastatic lymph node ratio (p = 0.014) observed in the H-BMI groups. Multivariate analyses indicated age, BMI, pathological tumor depth, distant metastases, metastatic lymph node ratio, and tumor size as independent prognostic factors. CONCLUSIONS: Our findings suggest that overweight patients were less likely to have tumors with aggressive features and can achieve ideal body weight following curative gastrectomy, possibly resulting in better long-term prognosis.
Obesity Surgery 02/2013; · 3.29 Impact Factor
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ABSTRACT: The miRNA-29 family of microRNAs (miRNAs), including miR-29a, miR-29b and miR-29c, was recently reported to be aberrantly expressed in multiple cancers. Increasing evidence shows that the abnormal expression of miR-29 family is associated with tumorigenesis and cancer progression, making miR-29s a well-analyzed group of miRNAs in cancer research. Here, in this review we aim to provide an overview of the role of miR-29 family in the pathophysiologic changes of cancer cells and the epigenetic and immune regulation through the biological function of miR-29s.
European journal of cell biology 01/2013; · 3.31 Impact Factor
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ABSTRACT: To investigate the role of neurotensin (NTS) in hepatocellular carcinoma (HCC) sub- grouping and the clinical and pathological significance of activation of NTS/IL-8 pathway in HCC.
The genome-wide gene expression profiling were conducted in 10 pairs of cancer tissues and corresponding normal adjacent tissues samples using Affymetrix GeneChip® Human Genome U133 Plus 2.0 microarray to screen differentially expressing genes and enrich dysfunctional activated pathways among different HCC subgroups. The levels of NTS protein and multiple inflammation and epithelial mesenchymal transition (EMT) related proteins, including IL-8, VEGF, MMP9, CD68, E-Cadherin, β-Catenin and Vimentin were examined in 64 cases of paraffin-embedded HCC samples using immunohistochemistry (IHC) staining method. The clinical outcome and overall survival (OS) were compared.
A subgroup of HCC characterized by up-regulated NTS expression was accompanied by up-regulated inflammatory responses and EMT. The direct interaction between NTS and IL-8 was identified by pathway enrichment analysis. Significantly increased IL-8 protein was confirmed in 90.91% of NTS(+) HCC samples and significantly positively correlated to the levels of NTS protein in cancer tissues (P = 0.036), which implied activation of NTS/IL-8 pathway in HCC. The levels of VEGF and MMP9 correlated with co-expression of NTS and IL-8. Increased infiltration of CD68(+) macrophages and more cancer cells displaying EMT features were found in NTS(+)IL-8(+) samples. The co-expression of NTS and IL-8 in cancer significantly correlated with the clinical outcomes, as the mortality rate of NTS(+)IL-8(+) HCC patients is 2.5-fold higher than the others after the surgery (P = 0.022). Accordingly, the OS of NTS(+)IL-8(+) HCC patients significantly decreased who are under a higher hazard of death at an expected hazard ratio (HR) of 3.457.
Dysfunctional activation of the NTS/IL-8 pathway was detected in HCC which is associated with increased inflammatory response in microenvironment, enhanced EMT in cancer, and worse prognosis in HCC patients.
PLoS ONE 01/2013; 8(2):e56069. · 4.09 Impact Factor
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ABSTRACT: Cytokine-induced killer (CIK) cells show cytolytic activity against tumor. The purpose of this study was to evaluate the antitumor effect of dendritic cell (DC)-activated CIK cells in vitro and their clinical efficacy of DC-activated CIK cells in combination with chemotherapy (abbreviated below as chemotherapy plus DC + CIK) in patients with advanced non-small-cell lung cancer (NSCLC). A paired study was performed between 61 patients treated with chemotherapy alone (group 1) and 61 patients treated with chemotherapy plus DC + CIK cells (group 2). In group 2, 36 patients with adenocarcinoma and 18 patients with squamous cell carcinoma were analyzed for the survival rate. Compared to unstimulated CIK cells, DC-activated CIK cells significantly enhanced antitumor activity, increased the ratio of CD3(+)CD56(+) cells, promoted cell proliferation and lessened cell apoptosis. In the paired study, the 1- and 2-year overall survival rates in group 2 were 57.2 and 27.0 %, which were significantly higher than that of group 1 (37.3 and 10.1 %) (P < 0.05). There was no significant difference in the survival rate between the adenocarcinoma and squamous carcinoma patients in group 2. The present study suggests that DC-activated CIK cell has enhanced antitumor effects and chemotherapy plus DC + CIK cells improved the clinical outcomes of chemotherapy for advanced NSCLC patients.
Cancer Immunology and Immunotherapy 06/2012; · 3.70 Impact Factor
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ABSTRACT: Glioma is one of the most malignant tumors in the central nervous system. As a peroxisome proliferator-activated receptor γ (PPAR-γ) activator, the thiazolidinediones (TZDs) induce growth arrest and cell death in a broad spectrum of tumor cells. In this study, we investigated the role of rosiglitazone in glioma cells. We found that rosiglitazone, a member of TZDs, suppresses growth of human glioma cell lines U87 and U251. Rosiglitazone also induces cell cycle arrest and apoptosis, which may be the mechanism of its anti-proliferation effect. Next, we found that rosiglitazone suppresses the expression of TGF-beta and its receptor TGF-betaR2, and suppresses phosphorylation of Smad3. Rosiglitazone also inhibits formation of the Smad3/Smad4 complex. Furthermore, Rosiglitazone affects the expression of Smad3/Smad4 associated regulators of gene expression, including p21 and c-Myc. These results suggest that rosiglitazone suppresses growth and cell cycle of human glioma cells by blocking the TGF-beta mediated pathway.
Neurochemical Research 06/2012; 37(10):2076-84. · 2.24 Impact Factor
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ABSTRACT: OBJECTIVE: Cytokine-induced killer (CIK) cells have the ability to kill tumor in vitro and in vivo. This study was designed to evaluate the clinical efficacy of CIK cell immunotherapy following regular chemotherapy in patients with non-small cell lung cancer (NSCLC) after surgery. METHODS: A paired study, with 87 stage I-IV NSCLC patients in each group, was performed. Patients received either chemotherapy (arm 2) or chemotherapy in combination with autologous CIK cell immunotherapy (arm 1). Progression-free survival (PFS) and overall survival (OS) were evaluated. RESULTS: Of the 87 paired patients, 50 had early-stage disease (stage I-IIIA) and 37 had advanced-stage disease (stage IIIB-IV). Among early-stage patients, the distribution of 3-year PFS rate and median PFS time showed no statistical difference between the two groups (p = 0.259 and 0.093, respectively); however, the 3-year OS rate and median OS time in arm 1 were significantly higher than those in arm 2 (82 vs. 66 %; p = 0.049 and 73 vs. 53 months; p = 0.006, respectively). Among the advanced-stage patients, the 3-year PFS and OS rates of arm 1 were significantly higher than those of arm 2 (6 vs. 3 %; p < 0.001 and 31 vs. 3 %; p < 0.001, respectively); the median PFS and OS times in arm 1 were also significantly longer than those in arm 2 (13 vs. 6 months; p = 0.001 and 24 vs. 10 months; p < 0.001, respectively). Multivariate analyses indicated that the frequency of CIK cell immunotherapy was significantly associated with prolonged PFS (HR = 0.91; 95 % CI 0.85-0.98; p = 0.012) and OS (HR = 0.83; 95 % CI, 0.74-0.93; p = 0.001) in the arm 1. CONCLUSIONS: The data suggested that CIK cell immunotherapy could improve the efficacy of conventional chemotherapy in NSCLC patients, and increased frequency of CIK cell treatment could further enhance the beneficial effects. A multi-center randomized trial is being carried out in our hospital to further validate these findings.
Cancer Immunology and Immunotherapy 05/2012; · 3.70 Impact Factor
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ABSTRACT: The therapeutic benefit of the cytokine-induced killer (CIK) cells was unknown in the renal cell carcinoma (RCC). This prospectively randomized study was conducted to evaluate the effects of autologous CIK cell immunotherapy in patients with metastatic clear cell RCCs.
From June 2005 to June 2008, 148 patients with metastatic clear cell RCC were randomized to autologous CIK cell immunotherapy (arm 1, n = 74), or interleukin-2 treatment combination with IFN-α-2a (arm 2, n = 74). The primary endpoint was overall survival (OS) and secondary endpoint was progression-free survival (PFS) evaluated by Kaplan-Meier analyses and treatment HRs with the Cox proportional hazards model.
The 3-year PFS and OS in arm 1 were 18% and 61%, as compared with 12% and 23% in arm 2 (P = 0.031 and <0.001, respectively). The median PFS and OS in arm 1 were significantly longer than those in arm 2 (PFS, 12 vs. 8 months, P = 0.024; OS, 46 vs. 19 months, P < 0.001). Multivariate analyses indicated that the cycle count of CIK cell immunotherapy as a continuous variable was significantly associated with prolonged PFS [HR = 0.88; 95% confidence interval (CI), 0.84-0.93; P < 0.001] and OS (HR = 0.58; 95% CI, 0.48-0.69; P < 0.001) in arm 1.
The data suggested that CIK cell immunotherapy could improve the prognosis of metastatic clear cell RCC, and increased cycle count of CIK cell treatment could further enhance the beneficial effects.
Clinical Cancer Research 03/2012; 18(6):1751-9. · 7.74 Impact Factor
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ABSTRACT: There was established evidence that silencing the attenuator and activating the TLRs could activate the dendritic cells in synergic effects. In this study, we constructed a plasmid, namely pshS1NH, which encodes SOCS1-shRNA, NY-ESO-1-MAGE3 (HLA-A2*0201) fusion antigen and secretory HMGB1, an agent used to modify dendritic cells (DCs), aiming to generate potent DC vaccine against tumors. The SOCS1-shRNA could efficiently downregulate the expression of SOCS1, as indicated by real-time RT-PCR and Western blot. The fusion antigen was detected in the pshS1NH-DCs by PCR and Western blot. Simultaneously, HMGB1 level in the pshS1NH-DCs culture media was significantly higher than that in the control DCs culture media. Levels of Th1 cytokines in pshS1NH-DCs culture media, such as IL-1β, IL-6, TNF-α and IL-12p70, were dramatically higher than those in control DCs culture media. In addition, lymphocytes co-cultured with pshS1NH-DCs secreted dramatically higher level of IFN-γ, whereas no difference was detected in IL-4 levels. Taken together, these data suggest that pshS1NH-DCs may be a potential adjuvant immunotherapy for cancers in clinical applications.
Cancer Immunology and Immunotherapy 02/2012; 61(10):1653-61. · 3.70 Impact Factor
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ABSTRACT: The concept of targeting antigens selectively expressed on the surface of tumor capillary endothelial cells or in tumor stroma has emerged as a promising strategy for cancer therapeutics. Identification of stromal targets for anticancer therapy and development of selective inhibitors of these targets are of great clinical interest. Fibroblast activation protein (FAP), a member of the serine protease family, selectively expressed in the stromal fibroblasts associated with epithelial cancers, whereas with low or undetectable expression in the resting fibroblasts of normal adult tissues. The proteolytic activity of FAP has been shown to support tumor growth and proliferation, making it a potential target for novel anticancer therapies, such as those by immune-based approaches.
Cancer biology & therapy 02/2012; 13(3):123-9. · 2.64 Impact Factor
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ABSTRACT: The inflammatory enzyme indoleamine 2, 3-dioxygenase (IDO) participates in immune tolerance and promotes immune escape of IDO+ tumors. A recent hypothesis suggested that IDO may contribute to the differentiation of new T regulatory cells (Tregs) from naive CD4+ T cells. In this study we investigated the role of IDO in induction of immunosuppression in breast cancer by increasing the apoptosis of T cells and the proportion of Tregs.
An IDO expression plasmid was constructed and Chinese hamster ovary (CHO) cells were stably transfected with human IDO. Purified CD3+ T cells were isolated from the peripheral blood monouclear cells of breast cancer patients. After co-culturing IDO expressing or untransfected (control) CHO cells with T cells, T cells apoptosis were determined by flow cytometry analysis and annexin-V and PI staining. The proportion of the regulatory T cell (Tregs [CD4 + CD25 + CD127⁻]) subset was measured by flow cytometry analysis. T cells total RNA and cellular protein samples were isolated for detecting Foxp3 gene and protein expression.
IDO transgenic CHO cells yielded high levels of IDO enzymatic activity, resulting in complete depletion of tryptophan from the culture medium. We found that apoptosis occurred in 79.07 ± 8.13% of CD3+T cells after co-cultured with IDO+ CHO cells for 3 days and the proportion of CD4 + CD25 + CD127⁻ T cells increased from 3.43 ± 1.07% to 8.98 ± 1.88% (P < 0.05) as well. The specific inhibitor of IDO,1-MT efficiently reversed enhancement of T cells apoptosis and amplification of Tregs in vitro. Increased expression of Foxp3, a key molecular marker of Tregs, was confirmed by RT-PCR, real-time RT-PCR and Western blot analysis at the same time.
These results suggest that IDO helps to create a tolerogenic milieu in breast tumors by directly inducing T cell apoptosis and enhancing Treg-mediated immunosuppression.
Journal of Experimental & Clinical Cancer Research 09/2011; 30:82. · 2.15 Impact Factor
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ABSTRACT: Cytokine-induced killer cells (CIKs) are heterogenous antitumor effectors including interferon gamma (IFN-γ)-amplified CD3(+)CD56(+) cells. CH-296 has been shown to stimulate T-cell proliferation in the presence of T cell receptor (TCR)-stimulating signals. The purpose of this study was to investigate the synergistic effect of CH-296 and IFN-γ on expansion of CIKs for treating patients with advanced-stage malignant solid tumors.
CIKs were cultured with immobilized CH-296 in the presence (retronectin [RN]-CIKs) or absence of IFN-γ (RN-CIKs/del) for 14 days. Proliferation, apoptosis, phenotype, and cytotoxicity were detected. Twenty (20) patients (18 patients with stage IV solid tumors) received three cycles of RN-CIKs treatment. The clinical responses were evaluated using Karnofsky Performance Status scoring and computed-tomography scanning.
CH-296 promoted CIKs expansion in a time-dependent manner by inhibiting apoptosis and increasing proliferation. Costimulation of CH-296 and IFN-γ amplified more antitumor effectors of CIKs with activated T-cell phenotype, which displayed potent cytotoxicity and increased cytokines secretion upon antigen priming. Sixteen (16) patients receiving RN-CIKs experienced relief of clinical symptoms. The overall clinical response rate was 65% (13/20) and the mean overall survival was 16.95±6.10 months. No severe adverse events were observed in the clinical trial.
CH-296 and IFN-γ synergistically promote antitumor efficiency of CIKs by increasing proliferation, inhibiting apoptosis, and enhancing cytotoxicity.
Cancer Biotherapy & Radiopharmaceuticals 08/2011; 26(4):485-94. · 1.44 Impact Factor
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ABSTRACT: Expansion of CD4+CD25+ regulatory T cells (Tregs) in tumor microenvironment was one of the mechanisms by which cancer cells escaped host defense. Thymic stromal lymphopoietin (TSLP) contributes to the generation of natural Tregs in thymus. Therefore, the purpose of this report was to investigate the role of TSLP in the increasing prevalence of Tregs in lung cancer microenvironment. The expression ratio of TSLP protein in tumor tissues was significantly increased compared with that in benign lesion and non-cancer lung tissue. The prevalence of Tregs in tumor microenvironment was correlated with the expression of TSLP in lung cancer. Dendritic cells (DCs) were induced from peripheral blood mononuclear cells (PBMCs) collected from lung cancer patients and left unstimulated (imDCs) or exposed to hTSLP (TSLP-DCs) or LPS (LPS-DCs). TSLP-DCs expressed intermediate levels of CD83 and high levels of CD86, CD11C, and HLA-DR, which showed a characteristic of less mature DCs. TSLP-DCs secreted low levels of IL-6, IL-12, IL-10, TNF-α and IFN-γ, and high levels of TGF-β and MDC. The percentage of Tregs in CD4+CD25- T cells cocultured with TSLP-DCs group was statistically higher than that of LPS-DCs and imDCs. Transwell assays showed that TSLP-DCs exhibited increased ability to attract the migration of CD4+CD25- Tregs, when compared with imDCs. These results indicated that TSLP proteins were expressed in lung tumor tissue and correlated with the prevalence of Tregs. TSLP-DCs could induce CD4+CD25- T cells to differentiate into CD4+CD25+foxp3+ T cells and the migration of CD4+CD25+ T cells.
Cancer Immunology and Immunotherapy 06/2011; 60(11):1587-96. · 3.70 Impact Factor
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ABSTRACT: To study the role of indoleamine 2,3-dioxygenase (IDO) in immune response and immune escape in gastric cancer, the human IDO gene was cloned by reverse transcription-polymerase chain reaction (RT-PCR) and inserted into the pIRES2-EGFP vector to construct the IDO expression vector (pIRES2-EGFP-IDO). BGC-823 cells were transfected with the vector by electroporation and selected stable expression with G418. IDO expression was determined by RT-PCR and Western blot analysis. The enzymatic activity of IDO was estimated by determining tryptophan and kynurenine concentrations in the cell culture medium by an amino acid analyzer. To assess the effect of IDO on T cell-mediated cytotoxicity and proliferation, T cells from patients with gastric cancer were co-cultured with the IDO-transfected BGC-823 cells in the presence or absence of 1-MT, a competitive inhibitor of IDO. Cells transfected with the vector expressed high levels of IDO mRNA and protein, and a significantly higher level of kynurenic acid was detected in the culture medium of the transfected cells compared to the non-transfected cells (P<0.001). T cells co-cultured with the IDO-transfected cells exhibited significantly lower cytotoxicity compared to the control group (P<0.05). Additionally, IDO-transfected cells treated with 1-MT exhibited higher toxicity compared to the untreated IDO-transfected cells (P<0.01). We conclude that IDO plays a key role in gastric cancer immune suppression, possibly by inhibiting T cell-mediated cytotoxicity and proliferation in vitro.
Molecular Medicine Reports 01/2011; 4(1):169-73. · 0.42 Impact Factor
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ABSTRACT: IDO has been reported to induce immunotolerance and promote metastasis in solid malignancy, but the mechanisms involved were not fully understood. In this study, the expression of IDO in primary breast cancer was examined and the correlation between the expression levels of IDO and the densities of Foxp3(+) Tregs in situ was studied. The IDO stably-expressing CHO cells(IDO/CHO) were generated to evaluate the induction of Foxp3(+) Tregs after coculturing with CD3(+) T cells in vitro. The IDO expression in cancer was higher than that in benign diseases both at RNA and protein levels. The IDO expression was significantly upregulated in tumors of more advanced stages and with more extensive lymph node metastasis, and displayed positive linear correlation with the density of Foxp3(+) Tregs. We further demonstrated that CD4(+)CD25(+)CD127(-) Tregs could be amplified by coculturing CD3(+) T cells with IDO/CHO cells in vitro which displayed increasing Foxp3 expression both at mRNA and protein levels. Our results implied that up-regulation of IDO in primary breast cancer may inhibit local immune surveillance and promote metastasis by favoring development and infiltration of Foxp3(+) Tregs in the tumor microenvironment.
Clinical and Developmental Immunology 01/2011; 2011:469135. · 1.84 Impact Factor
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ABSTRACT: Killer immunoglobulin-like receptor (KIR)-ligand incompatibility in the graft-versus-host direction is associated with improved outcome in patients receiving hematopoietic stem cell transplants. Fetal-maternal microchimerism has been suggested to mediate acquired fetal-maternal tolerance. The goal of this study was to determine the clinical efficacy of KIR-ligand incompatibility and fetal-maternal microchimerism for interleukin-2-activated haploidentical peripheral blood stem cells (haplo-PBSCs) treatment for patients with advanced solid cancer. Forty-two (42) patients with advanced stage of solid cancer and refractory to standard chemotherapy were treated with haplo-PBSCs donated by their parents or children. Human leukocyte antigen typing, fetal-maternal microchimerism status, and engraftment were detected. Clinical outcomes including overall survival (OS), progression-free survival (PFS), and Karnofsky Performance Status (KPS) level were evaluated. Patients receiving haplo-PBSCs treatment with KIR-ligand incompatibility in the graft-versus-host direction had higher probability of OS (26.8 ± 3.1 months) and PFS (13.4 ± 1.3 months) when compared with those with KIR ligand compatibility (OS: 17.4 ± 3.0 months, p < 0.05 and PSF: 8.0 ± 0.9 months, p < 0.05). Further, OS (31.2 ± 4.3 months), PFS (14.7 ± 2.2 months), and KPS increase (27 points) in the microchimerism-positive group was improved compared with that in the microchimerism-negative group (OS: 16.9 ± 3.8 months, p < 0.01, PFS: 5.6 ± 1.4 months, p < 0.01, and KPS increase: 15 points, p < 0.01). Therefore, KIR-ligand incompatibility and fetal-maternal microchimerism are associated with better outcome for haplo-PBSCs treatment.
Cancer Biotherapy & Radiopharmaceuticals 12/2010; 25(6):741-6. · 1.44 Impact Factor
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ABSTRACT: Alloreactive NK cells (Allo-NKs) have been shown to exert advantageous effects on the outcomes of haploidentical hematopoietic stem cell transplantation (Haplo-HSCT) for cancer treatment. However, the mechanisms of action of Allo-NKs remain unclear. We established a novel Haplo-HSCT conditioning regimen composed of Allo-NKs and a low dose of immunosuppressive drugs (Allo-NKs + Chemo) to investigate alternative mechanisms besides direct cytotoxicity. The inhibitory effects of different cell subsets on the donor-recipient mixed lymphocyte reactions (MLRs) were evaluated after Haplo-HSCT. The quantities and functions of CD4(+) CD25(+) regulatory T cells (Tregs) and dendritic cells (DCs) in the spleen and the thymus were examined. Our results showed that the Allo-NKs + Chemo regimen induced systemic tolerance, and that CD4(+) CD25(+) Tregs played a significant role in inducing and maintaining systemic tolerance after Haplo-HSCT. Alloreactive NK cells promoted the expansion of recipient-derived CD4(+) CD25(+) CD127(-) Tregs in the thymus and the spleen which could be amplified in vitro by the immature donor-derived DC subset isolated from the thymus of Allo-NKs + Chemo-treated mice. Our findings suggested that Allo-NKs are capable of inducing systemic tolerance after Haplo-HSCT by assembling donor-derived immature DCs to expand recipient-derived Treg cells in the thymus.
Transplant International 11/2010; 24(2):201-12. · 2.92 Impact Factor
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ABSTRACT: Indoleamine 2,3-dioxygenase (IDO), a tryptophan catabolic enzyme, plays an important role in immune escape through suppressing T-cell function. Since Vav1 signaling pathway regulates T cell homeostasis, this study was designed to test the hypothesis that IDO induces T-cell immunosuppression through inhibiting Vav1 signaling.
We found that IDO produced by IDO stably expressing CHO cells significantly inhibited interleukin (IL)-2 expression and proliferative response in T cells and increased apoptosis of T cells. IDO suppressed Vav1 mRNA and protein production in T cells. Furthermore, IDO inhibited TCR activation-induced Vav1 phosphorylation, which represents Vav1's activation state in T cells. These effects on T-cells induced by co-culture of CHO/IDO with T cells were attenuated by 1-MT.
Chinese hamster ovary (CHO) cells were stably transfected with human IDO (CHO/IDO). CD3(+) T cells were isolated from human peripheral blood monouclear cells. After co-culture of CHO/IDO cells with T cells in the presence or absence of an anti-CD3 antibody to activate T cell receptor (TCR) and/or 1-methyl-L-tryptophan (1-MT) to inhibit IDO activity, T cell proliferation and apoptosis were determined. T cell total RNA and cellular protein samples were isolated for detecting Vav1 gene and protein expression and activation state.
The inhibitory effects of IDO on T cell immune responses may be through downregulation of Vav1 protein expression and activation. These studies provide insight into understanding the mechanisms of immune escape induced by IDO and therapeutic application of IDO inhibitors for cancer treatment.
Cancer biology & therapy 08/2009; 8(14):1402-8. · 2.64 Impact Factor
