[Show abstract][Hide abstract] ABSTRACT: A meta-analysis was performed to augment the insufficient data on the impact of mutative EGFR downstream phosphatidylinositol-3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways on the clinical efficiency of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment of non-small cell lung cancer (NSCLC) patients.
Network databases were explored in April, 2015. Papers that investigated the clinical outcomes of NSCLC patients treated with EGFR-TKIs according to the status of K-ras and/or PIK3CA gene mutation were included. A quantitative meta-analysis was conducted using standard statistical methods. Odds ratios (ORs) for objective response rate (ORR) and hazard ratios (HRs) for progression-free survival (PFS) and overall survival (OS) were calculated.
Mutation in K-ras significantly predicted poor ORR [OR =0.22; 95% confidence interval (CI), 0.13-0.35], shorter PFS (HR =1.56; 95% CI, 1.27-1.92), and shorter OS (HR =1.59; 95% CI, 1.33-1.91) in NSCLC patients treated with EGFR-TKIs. Mutant PIK3CA significantly predicted shorter OS (HR =1.83; 95% CI, 1.05-3.20), showed poor ORR (OR =0.70; 95% CI, 0.22-2.18), and shorter PFS (HR =1.79; 95% CI, 0.91-3.53) in NSCLC patients treated with EGFR-TKIs.
K-ras mutation adversely affected the clinical response and survival of NSCLC patients treated with EGFR-TKIs. PIK3CA mutation showed similar trends. In addition to EGFR, adding K-ras and PIK3CA as routine gene biomarkers in clinical genetic analysis is valuable to optimize the effectiveness of EGFR-TKI regimens and identify optimal patients who will benefit from EGFR-TKI treatment.
[Show abstract][Hide abstract] ABSTRACT: The hallmark of tumor microenvironment is that it makes up of numerous immunomodulatory cells and factors which exert essential roles in immunoprotection and immunosuppression in addition to tumor cells. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells reported to promote immunosuppression and angiogenesis and facilitate tumor metastasis and invasion. The wide scope of MDSCs functional activities make these cells promising targets for effective cancer treatments. In this review, we briefly discuss the origin, subpopulation, and functions of MDSCs, as well as the potential to target these cells for therapeutic benefit. We focus on the underlying molecular mechanisms of these drugs targeting MDSCs, mainly from the standpoint of molecules related to drug targets.
[Show abstract][Hide abstract] ABSTRACT: Purposes Osteopontin (OPN), an extracellular matrix-secreted phosphorylated glycoprotein, has been reported overexpressed in many solid tumors. As an important part of lung cancer, the high recurrence of non-small cell lung cancer (NSCLC) also attracted great attention of scientists. Methods In this study, we investigated the expression of OPN and the relationship with prognosis of NSCLC patients. We measured the expression of OPN among 163 NSCLC samples by immunohistochemical method and compared the expression of these 28 matched cDNA between tumor and peritumoral tissue by real-time polymerase chain reaction. Results We demonstrated that the percentages of positive OPN expression is 66.8 % and OPN expression in tumor site was much higher than the tissue adjacent to carcinoma (p = 0.0046). By further analysis, we found that OPN expression was significantly correlated with poor prognosis of NSCLC. Moreover, for early-stage patients, OS and DFS rates of OPN (−) group were significantly higher than OPN (+) group. For advanced-stage patients, OPN expression was only associated with OS rates. Conclusions These results suggest that OPN is commonly expressed in NSCLC and may guide the evaluation of prognosis with NSCLC, especially for early-stage patients.
Journal of Cancer Research and Clinical Oncology 01/2015; DOI:10.1007/s00432-014-1902-1 · 3.01 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Castleman's disease (CD) is a rare lymphoproliferative disorder characterized by atypical lymph node follicular hyperplasia. Subsequential occurrence of CD and cancers has been rarely reported and interpretations of the relationship are contentious. An asymptomatic 70-year-old man was found to have a left-sided hilar mass during routine follow-up after a radical right nephrectomy for clear cell carcinoma, raising suspicions of lung metastasis. Because there was no sign of recurrence in the original operative region, he underwent wedge resection of the left lung and lymph nodes dissection. Histology showed typical features of HVCD. Herein, we emphasize careful histopathology and complete resection of CD. We speculate that subsequential occurrence of CD and cancers may not be coincidental and warrants further exploration.
[Show abstract][Hide abstract] ABSTRACT: Telomeres are specific nucleoprotein structures at the end of a eukaryotic chromosomes characterized by repeats of the sequence TTAGGG and regulated by the enzyme telomerase which prevents their degradation, loss, rearrangement and end-to-end fusion. During activation, T lymphocytes actively divide, albeit through only a finite number of cell divisions due to shortening of telomeres. However, studies have demonstrated that human telomerase reverse transcriptase (hTERT), thought to be the major component regulating telomerase activity, can enhance the proliferation of T cells when overexpressed. There are many treatments for cancers, most of which are targeting the telomere and telomerase of tumor cells. However, the hTERT-transduced T cells improve their potential for proliferation, making them an appropriate cell resource for tumor adoptive immunotherapy, a procedure whereby T cells are isolated from patients, expanded ex vivo and eventually delivered back into the patients, provides a new approach for tumor therapy through improved overall survival rates in cancer patients. In this review, we will focus on the telomerase activity in T cells, the regulation of telomerase activity, and hTERT-transduced T cells used in adoptive immunotherapy for cancer.
[Show abstract][Hide abstract] ABSTRACT: Cytokine-induced killer (CIK) cells have shown cytolytic ability against ovarian cancer cells in vitro and in vivo. This study was aimed to evaluate the clinical efficacy of maintenance therapy of CIK cells in patients with advanced epithelial ovarian cancer after first-line treatment. A paired study was performed in patients with stages IIB-IV epithelial ovarian cancer after cytoreductive surgery followed by 6-8 courses of carboplatin/paclitaxel chemotherapy. A total of 92 patients who achieved complete remission after first-line treatment were enrolled in this study. Forty-six patients in the treatment group received CIK cells transfusion monthly, whereas the other 46 patients in the control group received observation with follow-up. Progression-free survival (PFS), overall survival (OS), and toxicity were evaluated. Our results showed that median PFS was 37.7 months in the treatment group and 22.2 months in the control group (P=0.004). However, although median OS in the treatment group (61.5 mo) was longer than that in the control group (55.9 mo), there was no significant difference (P=0.289). The subgroup analysis revealed that the survival advantage of PFS from immunotherapy was independent of the extent of debulking surgery and pathologic stage. After 2 courses of CIK cells transfusion, the proportion of CD4CD25CD127 regular T cells in the peripheral blood significantly decreased (P=0.006). No grades III and IV adverse reaction were found during CIK cells infusion. Maintenance therapy with CIK cells improved the PFS in patients with advanced ovarian cancer after first-line treatment with slight side effects. However, the benefits with respect to OS are still pending.
[Show abstract][Hide abstract] ABSTRACT: This prospective study aims to explore the benefit of cytokine-induced killer cell (CIK) treatment in hepatocellular carcinoma patients, which has not yet been thoroughly studied before.
From January 2004 to May 2009, 132 patients who were initially diagnosed with hepatocellular carcinoma of Barcelona Clinic Liver Cancer (BCLC) stage A, B or C, Child-Pugh scores of A or B and without prior treatment were enrolled in the study. Patients were randomly assigned to either arm 1 (n = 66) to receive CIK treatment plus standard treatment, or arm 2 (n = 66) to receive standard treatment only. The primary end point was overall survival (OS) and the secondary endpoint was progression-free survival as evaluated by Kaplan-Meier analyses and treatment hazard ratios with the Cox proportional hazards model.
The 1-year (OS: 74.2 % vs. 50.0 %, 95 % CI: 63.6-84.8 % vs. 37.8-62.2, p = 0.002), 2-year (OS: 53.0 % vs. 30.3 %, 95 % CI: 40.8-65.2 % vs. 19.1-41.5 %, p = 0.002), 3-year (OS: 42.4 % vs. 24.2 %, 95 % CI: 30.4-54.4 % vs. 13.8-34.6 %, p = 0.005) and median overall and progression-free survivals of arm 1 patients were significantly higher than those of arm 2. Therefore, in patients who are not suitable for surgery, significant benefit is obtained from CIK treatment. The main adverse effects of CIK included fever, allergy and headache pain.
Hepatocellular carcinoma patients who were not suitable for surgery demonstrate prolonged overall and progression-free survival from CIK treatment.
[Show abstract][Hide abstract] ABSTRACT: Cytokine-induced killer (CIK) cells, which display both potent anti-tumor ability of T lymphocytes and non-majorhistocompatibility complex (MHC) restricted killingtumor cells capacity of natural killer (NK) cells are capable of recognizing and lysing a broad array of tumor targets. They have begun to be used in clinical care with good prospects for treatment success. CIK cells are a heterogeneous cell population that contain CD3(+)CD56(+) cells, CD3(-)CD56(+) natural killer (NK) cells and CD3(+)CD56(-) T cells on which much attention has been focused. This review will summarize the connections and differences among CD3(+)CD56(+)CIK cells, CD3(-)CD56(+) NK cells and CD3(+)CD56(-) T cells in the following aspects: the main cell surface molecule, killing mechanism, and clinical applications so that treatment with CIK cells can be optimized and further to enhance the antitumor effect.
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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; 190(7). DOI:10.4049/jimmunol.1201449 · 5.36 Impact Factor
[Show abstract][Hide abstract] 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; 23(5). DOI:10.1007/s11695-012-0847-1 · 3.74 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Dendritic cells (DCs) have traditionally been viewed as constituting an 'information management' system that functions solely to integrate a diverse array of incoming signals, in order to induce immune reactivity. In recent years, however, there has been a shift towards viewing these cells as key regulators in the orchestration of immunological tolerance, with increasing recognition that they are capable of suppressing T-cell responses depending on signalling processes and localised biochemical conditions. Indoleamine 2,3-dioxygenase (IDO) competent (IDO+) DCs are a subset of human DCs which are programmed to a tolerogenic state and play a vital role in establishing and maintaining a tumour-suppressing milieu. The expression of IDO in these DCs represents a key mechanism responsible for inducing the tolerogenic state. However, the mechanisms by which IDO becomes dysregulated in this subset of DCs have not yet been described. In this review, the function of IDO+ DCs within the cancer-tolerogenic milieu, as well as the signals responsible for expression of IDO in this subset, will be discussed.
Current cancer drug targets 01/2013; 13(3). DOI:10.2174/15680096113139990073 · 3.58 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: MicroRNAs (MiRNAs) are small non-coding RNAs that regulate their target genes expression at the post-transcriptional level. As accumulating properties of miR-205 have been identified, complex roles of miR-205 in tumor initiation and progression are emerging. MiR-205 acts either as a tumor suppressor through inhibiting proliferation and invasion, or as an oncogene through facilitating tumor initiation and proliferation, depending on the specific tumor context and target genes. In this review, we focus on the properties of miR-205 in cancers to shed light on better management of various fatal malignancies. Moreover, we discuss epigenetics that may account for the fluctuation of miR-205 expression. In addition, we sketch a network of miR-205 and its targets to further elucidate the mechanisms through which miR-205 exerts its multiple functions.
European journal of cell biology 12/2012; 92(2). DOI:10.1016/j.ejcb.2012.11.002 · 3.70 Impact Factor
[Show abstract][Hide abstract] 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; 62(1). DOI:10.1007/s00262-012-1311-8 · 3.94 Impact Factor
[Show abstract][Hide abstract] 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; 61(11). DOI:10.1007/s00262-012-1260-2 · 3.94 Impact Factor
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] ABSTRACT: Traditional immunotherapy for patients with refractory metastatic renal cell carcinoma (RCC) is limited because the tumors themselves induce immunosuppression. The aim of this article was to evaluate the clinical efficacy of the infusion of a high dose of interleukin (IL)-2-activated allogeneic haploidentical peripheral blood stem cells (haplo-PBSCs) in patients with advanced intractable RCC. Ten advanced RCC patients and their haploidentical relatives, who were haplo-PBSC donors, were enrolled in this study. All patients accepted one cycle of activated haplo-PBSCs. The clinical and immunologic responses were evaluated. A range from 2.3 to 5.5×10(10) of activated haplo-PBSCs were harvested after exposure to recombinant human IL-2 (rhIL-2), along with a significant increase in the proportion of natural killer cells and activated lymphocytes (CD69+ and CD25+). Enhanced cytotoxicity of haplo-PBSCs for RCC was also observed. After treatment, 2 (2/10) cases of partial remission, 6 (6/10) cases of stable disease, and 2 (2/10) cases of progressive disease were identified in these 10 patients. The median progression-free survival of the 10 patients was 5.5 months (3-14 months). The adoptive transfusion of IL-2-activated haplo-PBSCs can induce sustained antitumor effects for advanced intractable RCC patients who have had no response to conventional immunotherapy.
[Show abstract][Hide abstract] 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. DOI:10.1007/s00262-011-1059-6 · 3.94 Impact Factor
[Show abstract][Hide abstract] 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.