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1.
The generation of antitumour immunity depends on the nature of dendritic cell (DC)-tumour interactions. These have been studied mostly by using in vitro-derived DC which may not reflect the natural biology of DC in vivo. In breast cancer, only one report has compared blood DC at different stages and no longitudinal evaluation has been performed. Here we conducted three cross-sectional and one one-year longitudinal assessments of blood DC in patients with early (stage I/II, n=137) and advanced (stage IV, n=36) disease compared to healthy controls (n=66). Patients with advanced disease exhibit markedly reduced blood DC counts at diagnosis. Patients with early disease show minimally reduced counts at diagnosis but a prolonged period (1 year) of marked DC suppression after tumour resection. While differing in frequency, DC from both patients with early and advanced disease exhibit reduced expression of CD86 and HLA-DR and decreased immunostimulatory capacities. Finally, by comparing a range of clinically available maturation stimuli, we demonstrate that conditioning with soluble CD40L induces the highest level of maturation and improved T-cell priming. We conclude that although circulating DC are compromised by loco-regional and systemic breast cancer, they respond vigorously to ex vivo conditioning, thus enhancing their immunostimulatory capacity and potential for immunotherapy.  相似文献   

2.
The present study aimed to investigate the efficacy of a myeloid dendritic cell (mDCs) and plasmacytoid (p)DC combined vaccine loaded with heat-treated cancer cell lysates against lung cancer cells. The mDCs and pDCs were selected using magnetic bead sorting. Antigen loading was performed by adding heat-treated Lewis lung cancer cell lysates to mDC, pDC or mDC+pDC (1:1). Surface expression of CD80, CD86, CD40 and major histocompatibility complex (MHC)-II molecules were determined using flow cytometry, and the secretion of cytokines IL-12, IL-6 and TNF-α were assessed using ELISA assays. The effect of the mDC and pDC vaccine on cytotoxic T lymphocytes (CTLs) against tumor cells was investigated. Tumor-bearing nude mice were intravenously injected with the mDC and pDC combined vaccine. Tumor tissues were collected for hematoxylin and eosin and TUNEL staining. Loading with tumor cell lysate significantly upregulated the surface expression of costimulatory molecules MHC-II on DCs and enhanced secretions of IL-6, IL-12 and TNF-α by DCs. In addition, the tumor cell lysate-loaded mDC and pDC combined vaccine significantly promoted lymphocyte proliferation and enhanced CTL-mediated cytotoxicity against Lewis lung cancer cells compared with mDC or pDC treatment alone. Furthermore, intravenous injection of the mDC and pDC combined vaccine into tumor-bearing nude mice significantly inhibited subcutaneous tumor growth and induced necrosis and apoptosis within the tumor tissue. Overall, the pDC and mDC combination vaccine loaded with heat-treated Lewis lung cancer cell lysate had a synergistic effect on the induction of T lymphocyte proliferation and antitumor efficacy, which may be associated with the upregulation of co-stimulatory molecules and cytokine secretions.  相似文献   

3.
Breast cancer remains one of the most common malignant diseases in women in North America and Western Europe, yet therapies for the more aggressive estrogen independent tumors are limited and few model systems are available for the study of this type of breast cancer. In these studies, we characterized a novel estrogen independent breast cancer cell line, SUM-159PT. SUM-159PT cells are epithelial in origin, demonstrated by expression of cytokeratin 18. SUM-159PT cells are estrogen independent, demonstrated by lack of estrogen receptor (ER) protein and ER ligand binding studies. Furthermore, SUM-159PT cells injected subcutaneously or orthotopically are tumorigenic in ovariectomized athymic nude mice in the absence of estradiol supplementation. SUM-159PT cells are capable of invading through an 8m Matrigel membrane and display a stellate morphology in Matrigel, indicative of a metastatic phenotype. Correlating with this phenotype, we have detected secondary tumors upon inoculation of SUM-159PT cells into the mammary fat pad. To further investigate the metastatic potential of the SUM-159PT cells, we examined the expression of two proteins, vimentin and E-cadherin, implicated in the transition of carcinoma cells to a metastatic phenotype. Western blot and immunohistochemical analysis demonstrated that both SUM-159PT cells and xenografts express vimentin. No expression of E-cadherin was detected in SUM-159PT cells. Our data indicate that despite estrogen independence, SUM-159PT cells are growth inhibited in vitro by compounds such as 1,25(OH)2D3, transforming growth factor (TGF-), and the phorbol ester TPA. These studies indicate that SUM-159PT cells represent a good model system for the study of late stage estrogen independent, invasive breast cancer.  相似文献   

4.
Objective The aim of the study was to investigate the inhibitory effects of dendritic cells(DCs) loaded with resistant breast cancer antigens on breast cancer in nude mice. Methods A single-cell suspension was prepared from a primary breast cancer and chemotherapeutic drugs were screened using the ATP-PCA susceptibility testing system. Cancer cells were treated with 1/10 × IC50, 1/5 × IC50, 1/2 × IC50, 1 × IC50, and 2 × IC50 medium until their growth became steady in the 2 × IC50 medium. Peripheral blood mononuclear cells(PBMCs) were obtained from the peripheral blood of patients with leukapheresis. The obtained adherent cells were induced by granulocyte-macrophage colony-stimulating factor(GM-CSF) and interleukin-4(IL-4) to generate DCs, which carried resistant strain cell lysis compounds or non-treated cancer cell lysis compounds. The former mature DCs carried resistant breast tumor antigens. A breast tumor-bearing nude mouse model was established with these resistant strains and the mice were randomly divided in three groups. The mice in the treatment group were injected with DCs loaded with resistant breast cancer antigens. The control group consisted of mice injected with DCs loaded with primary tumor cell antigens and the blank group consisted of mice injected with the same volume of normal saline. Changes in the cancers were observed. Results After treatment with the effector cells, the cancer volume and weight were significantly different to those before treatment in every group of mice(P < 0.05). The tumor volume in the blank group was the largest(3.362 ± 0.068 cm3) and the tumor weight was 637.50 ± 59.398 mg. Compared to the blank group, the tumor volume in the experimental group was the smallest(1.273 ± 0.071 cm3) and the tumor weight was 206.81 ± 32.711 mg. Conclusion DCs loaded with resistant breast cancer antigens demonstrated a significant inhibition effect on the cancers of breast tumor-bearing nude mice.  相似文献   

5.
秦雪  李秀琴 《现代肿瘤医学》2016,(21):3459-3462
目的:探讨自体DC-CIK细胞疗法改善卵巢癌患者的预后及免疫功能的能力。方法:回顾性分析2014年1月至2015年12月在中国医科大学附属盛京医院均接受了规范的初始治疗、达到完全缓解(CR)的卵巢癌患者90例。分析比较其基本条件、免疫指标、无瘤生存时间及不良反应。结果:经DC-CIK生物免疫治疗的患者外周血CD3+、CD4+细胞百分率,CD3+、CD8+细胞百分率及CD4+/CD8+比值均上升,NK细胞即CD16+、CD56+细胞增多,同时随着疗程数的增多,升高的更加明显(P<0.05)。一线治疗后,单纯观察组平均无瘤生存时间为15.88±2.7个月明显少于DC-CIK生物免疫治疗组的22.5±4.13个月(P=0.039)。其中使用DC-CIK生物免疫治疗疗程≥5程的平均无瘤生存时间为27.25±4.53个月明显高于DC-CIK生物免疫治疗疗程≤4程的19.69±2.81个月,两者相比差异无明显统计学意义(P=0.412)。所有患者DC-CIK细胞治疗后血常规及肝肾功能检测与治疗前及单纯观察组患者相比无明显变化,也未见明显不良反应。结论:DC-CIK免疫治疗提高卵巢癌患者的免疫反应,改善卵巢癌患者预后,未见明显不良反应。  相似文献   

6.
Identification of tumor-specific target antigens has been a major hurdlefor the treatment of malignant disease by vaccination or immunotherapy. A second challenge has been the induction of therapeutically effective immune responses to these ‘self’ antigens. The recent recognition of dendritic cells as powerful antigen-presenting cells capable of inducing primary T-cell responses in vitro and in vivo – in combination with identification of tumor-specific antigens – has generated widespread interest in dendritic cell-based immunotherapy against a wide variety of tumors. In this review, a series of recently identified novel ovarian tumor antigens is discussed, and the potential for therapeutic dendritic cell vaccination targeted against these antigens is assessed.  相似文献   

7.
Progenipoietin (ProGP-4) is a chimeric molecule, exhibiting both Flt-3 and granulocyte-colony stimulating factor (G-CSF) receptor agonist activities. Subcutaneous administration of ProGP-4 to BALB/c mice at a dose of 40-100 microg/day for up to 12 consecutive days induces both CD11c(+) dendritic cells (DCs) and CD11c(-)/CD11b(+) granulocytes in spleen, blood and lymph nodes of treated animals. Peak numbers of all cell populations were observed on day 7 of treatment, with CD11c(+) DCs representing approximately 8% of total splenocytes at that time. Approximately 40-50% of these CD11c(+) cells were also able to endocytose and process the exogenous fluorescent antigen DQ-BSA. As a test of their therapeutic utility, freshly prepared CD11c(+) DCs were pulsed with a defined tumor-associated peptide epitope (murine p53(232-240)) and injected as a vaccine into BALB/c mice bearing day 7 established CMS4 sarcomas. Similarly prepared DCs were injected again 1 week later. Based on our results, we conclude that (i) both peptide-pulsed CD11c(+) DCs (harvested directly from ProGP-4 treated mice) and pulsed bone marrow-derived DCs effectively slow the growth of or mediate the regression (in 25 of 89 [28%] cases) of CMS4 tumors, and (ii) nonpulsed DCs mediated minimal or no therapeutic effect. These data support the ability of ProGP-4 to enhance the peripheral frequencies of DCs that exhibit therapeutic efficacy when applied as a vaccine to treat tumor-bearing animals.  相似文献   

8.
Summary The total number of mast cells and the number of such cells observed within and at the periphery of invasive breast cancers from 424 patients enrolled in protocol 4 of the National Surgical Adjuvant Breast Project were correlated with 38 other pathologic and 6 clinical features. High total mast cell counts as well as those within and at the periphery of the cancers were found to be significantly (p.05) associated with a patient age less than 50 years and the degree of tumor lymphoid cell reaction. The latter has also been found to be related to young age and other pathologic characteristics related to mast cell content. This suggests that the mast cells may simply represent another cell type of this reactive change. No differences in 10 year disease-free survival were detected in patients without mast cells and those exhibiting varying numbers of such cells. This information indicates that identifiable mast cells do not represent a prognostic pathologic discriminant in patients with breast cancer. However, this does not unequivocally exclude a role of mast cell secretory products, since only intact and not degranulated or disrupted forms of these cells can be counted.  相似文献   

9.
Dendritic cells (DCs) are described as professional antigen-presenting cells because of their superior T-cell stimulatory capacity. For this reason, attention is being focused on using DCs for clinical applications to treat cancer patients. Although preclinical studies are promising, the majority of clinical studies with DCs have not fulfilled the expectations, yet. The field of DC biology has progressed rapidly over the past years, leading to several options for the improvement of vaccination. Among the different parameters to investigate, this review focuses on the efficiency and biological and functional consequences of different gene transfer methods into different subsets of human DCs. Another important consideration for DC-based vaccination is the elucidation of the role of maturation and apoptosis during DC differentiation.  相似文献   

10.
Immunotherapy with dendritic cells for prostate cancer   总被引:2,自引:0,他引:2  
Radical prostatectomy for prostate cancer is followed by PSA recurrence in up to 40% of patients. One third of patients with biochemical relapse progress to uncurable metastatic disease. Therefore, alternative treatment modalities are needed both in the situation of PSA recurrence and in hormone‐refractory disease. Dendritic cells (DC) are the most powerful antigen‐presenting cells, able to prime naïve T‐cells and to break peripheral tolerance and thus induce tumor immune responses. More than 400 prostate cancer patients have been treated with DC‐based immunotherapy to date, and immune responses have been reported in two‐thirds of these, resulting in clinical responses in almost half of the patients treated. Most responses, however, were modest and transient. Therefore, mechanisms of treatment failure and possibilities to improve vaccination efficacy are being discussed. © 2007 Wiley‐Liss, Inc.  相似文献   

11.
Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer for which there is no effective treatment. Previously, we and others demonstrated that CXCR4 surface expression is an independent prognostic factor for disease relapse and survival in breast cancer. In this study, we investigated the effects of CXCR4 gene silencing on cisplatin chemosensitivity in human triple-negative breast cancer cell lines. We found that CXCR4 silencing significantly inhibited cell growth, decreased colony formation, and enhanced cisplatin sensitivity while overexpression of CXCR4 rendered cells more resistant to cisplatin. Moreover, the percentage of apoptosis and cell cycle arrest at the G2/M phase of cisplatin-treated CXCR4 knockdown cells was significantly higher than control cells. Furthermore, we demonstrated CXCR4 knockdown cells showed lower levels of mutant p53 and Bcl-2 protein than the control group, while also having higher levels of caspase-3 and Bax. However overexpression of CXCR4 had the reverse effect. In vivo experiments confirmed that downregulation of CXCR4 enhanced cisplatin anticancer activity in tumor-bearing mice, and that this enhanced anticancer activity is attributable to tumor cell apoptosis. Thus, this study indicates that CXCR4 can modulate cisplatin sensitivity in TNBC cells and suggests that CXCR4 may be a therapeutic target for TNBC.  相似文献   

12.
目的:探讨自体热休克凋亡细胞负载的树突状细胞(dendritic cells,DC)治疗大肠癌的临床疗效。方法:采用酶消化法从手术切除的14例大肠癌新鲜组织获得单细胞悬液,热休克处理后用桦脂酸诱导其凋亡制备成细胞抗原;采集外周静脉血,分离单个核细胞,经GM-CSF与IL-4体外诱导成未成熟树突状细胞,负载细胞抗原后制备成DC肿瘤疫苗;对14例大肠癌患者进行4个疗程的DC免疫治疗,观察患者不良反应、敏感程度、生存质量、生存时间、癌胚抗原等临床指标。结果:DC治疗大肠癌未出现明显不良反应,5例患者的DTH检测阳性;14例患者的平均CEA水平由治疗前的99.5ng/ml降至治疗后的71.4ng/ml(P〈0.05);治疗后血清中IL-2、IL-12及IFN-γ浓度均显著高于治疗前,具有统计学差异(P〈0.05);所有患者均生存1年,其中1例患者出现了短暂的后腹膜淋巴结缩小,持续3个月,第2年由于肿瘤的进展生存率下降,由80%降至20%;患者的KPS评分上升,与治疗前比较有所改善(P〈0.05)。结论:自体热休克凋亡细胞负载的DC治疗大肠癌在临床治疗中具较高安全性,可改善患者免疫功能,临床观察显示患者近期临床效果明显;为大肠癌的临床综合治疗提供了一种新方法。  相似文献   

13.
目的:探讨自体热休克凋亡细胞负载的树突状细胞(dendritic cells,DC)治疗大肠癌的临床疗效。方法:采用酶消化法从手术切除的14例大肠癌新鲜组织获得单细胞悬液,热休克处理后用桦脂酸诱导其凋亡制备成细胞抗原;采集外周静脉血,分离单个核细胞,经GM-CSF与IL-4体外诱导成未成熟树突状细胞,负载细胞抗原后制备成DC肿瘤疫苗;对14例大肠癌患者进行4个疗程的DC免疫治疗,观察患者不良反应、敏感程度、生存质量、生存时间、癌胚抗原等临床指标。结果:DC治疗大肠癌未出现明显不良反应,5例患者的DTH检测阳性;14例患者的平均CEA水平由治疗前的99.5ng/ml降至治疗后的71.4ng/ml(P<0.05);治疗后血清中IL-2、IL-12及IFN-γ浓度均显著高于治疗前,具有统计学差异(P<0.05);所有患者均生存1年,其中1例患者出现了短暂的后腹膜淋巴结缩小,持续3个月,第2年由于肿瘤的进展生存率下降,由80%降至20%;患者的KPS评分上升,与治疗前比较有所改善(P<0.05)。结论:自体热休克凋亡细胞负载的DC治疗大肠癌在临床治疗中具较高安全性,可改善患者免疫功能,临床观察显示患者近期临床效果明显;为大肠癌的临床综合治疗提供了一种新方法。  相似文献   

14.
Cyclooxygenase-2 (COX-2) is a rate-limiting enzyme in the synthesis of prostaglandins. It is over-expressed in multiple cancers and has been associated with diminished tumor immunity. Dendritic cells (DCs) are considered candidates for cancer immunotherapy due to their ability to process and present antigens to T cells and stimulate immune responses. However, DC-based vaccines have exhibited minimal effectiveness against established tumors. In this study, we evaluated the effect of short-term administration of the selective COX-2 inhibitor celecoxib on the efficacy of DC-based vaccines in preventing and treating established 4T1 murine mammary tumors. We show that dietary celecoxib alone significantly suppresses the growth of primary tumors and the incidence of lung metastases in the prophylactic setting but is less effective against pre-established tumors. However, we demonstrate that celecoxib administered after primary tumor establishment synergizes with tumor lysate-pulsed DC and the adjuvant, GM-CSF, to improve the antitumor immune response by suppressing primary tumor growth and markedly reducing the occurrence of lung metastases. This triple combination therapy elicits a tumor-specific immune response evidenced by elevated IFN-gamma and IL-4 secretion by CD4+ T cells and results in increased infiltration of CD4+ and CD8+ T cells to the tumor site. In addition, dietary celecoxib inhibits angiogenesis evidenced by decreased vascular proliferation within the tumor and serum vascular endothelial growth factor levels. These studies suggest that short-term celecoxib therapy in combination with DC vaccines may be safely used for treating metastatic breast cancer.  相似文献   

15.
The treatment and general care for women diagnosed with breast cancer has made a tremendous change and advance in the last decades. Better methods for early detection and screening of the disease, higher compliance of women to go for screening, an open social and political discourse of women and the health care team and others, are just a few that both enabled and are a result of this change. Nurses have been highly involved in these changes, which resulted in the specialization of nursing in the field of breast cancer. This article will focus on the main four points that influence the nursing specialist care, that is, the tailoring of treatment and the ability to offer women treatment which is more specific to their own cancer; the importance of the multidisciplinary team as providing a State of the Art care; the involvement of women in the decision-making regarding their treatment and the specific developing role of the specialist breast care nurse.  相似文献   

16.
乳腺癌干细胞(breast cancer stem cells,BCSCs)是导致乳腺癌发生、转移、耐药、复发等的重要原因。MicroRNAs(miRNAs)是近年来发现的一种非编码小分子RNA,可通过与靶标基因的3 '-非翻译区(3'-UTR)的完全或不完全配对,抑制靶标基因的翻译或降解靶标基因,从而发挥多种生物学功能。miRNAs在BCSCs中的异常表达可调控BCSCs的自我更新、抗凋亡、上皮间质转化(epithelial-mesenchymal transition,EMT)等生物学行为,从而促进乳腺癌的复发、转移。以miRNAs为研究靶点,为乳腺癌的诊断、预后及治疗提供了全新的思路。本文就近年来该方面的研究进展简要综述。  相似文献   

17.
Tumours have at least two mechanisms that can alter dendritic cell (DC) maturation and function. The first affects the ability of haematopoietic progenitors to differentiate into functional DCs; the second affects their differentiation from CD14+ monocytes, promoting an early but dysfunctional maturation. The aim of this study was to evaluate the in vivo relevance of these pathways in breast cancer patients. For this purpose, 53 patients with invasive breast cancer were compared to 68 healthy controls. To avoid isolation or culture procedures for enrichment of DCs, analyses were directly performed by flow cytometry on whole-blood samples. The expression of surface antigens and intracellular accumulation of regulatory cytokines upon LPS stimulation were evaluated. The number of DCs, and in particular of the myeloid subpopulation, was markedly reduced in cancer patients (P<0.001). Patient DCs were characterized by a more mature phenotype compared with controls (P=0.016), and had impaired production of IL-12 (P<0.001). These alterations were reverted by surgical resection of the tumour. To investigate the possible role of some tumour-related immunoactive soluble factors, we measured the plasmatic levels of vascular endothelial growth factor, IL-10 and spermine. A significant inverse correlation between spermine concentration and the percentage of DCs expressing IL-12 was found. Evidence was also obtained that in vitro exposure of monocyte-derived DCs to spermine promoted their activation and maturation, and impaired their function. Taken together, our results suggest that both the above-described mechanisms could concomitantly act in breast cancer to affect DC differentiation, and that spermine could be a mediator of dysfunctional maturation of DCs.  相似文献   

18.
Human cell lines are an important resource for research, and are often used as in vitro models of human diseases. In response to the mandate that all cells should be authenticated, we discovered that the MDA-MB-231 cells that were in use in our lab, did not validate based on the alleles of 9 different markers (STR Profile). We had been using this line as a model of triple negative breast cancer (TNBC) that has the ability to form tumors in immuno-compromised mice. Based on marker analysis, these cells most closely resembled the MCF10A line, which are a near diploid and normal mammary epithelial line. Yet, the original cells express carbonic anhydrase IX (CAIX) both constitutively and in response to hypoxia and are features that likely drive the aggressive nature of these cells. Thus, we sought to sub-purify CAIX-expressing cells using Fluorescence Activated Cell Sorting (FACS). These studies have revealed a new line of cells that we have name UFH-001, which have the TNBC phenotype, are positive for CAIX expression, both constitutively and in response to hypoxia, and behave aggressively in vivo. These cells may be useful for exploring mechanisms that underlie progression, migration, and metastasis of this phenotype. In addition, constitutive expression of CAIX allows its evaluation as a therapeutic target, both in vivo and in vitro.  相似文献   

19.
BACKGROUND: Further optimization of dendritic cell (DC)-based vaccines is required clinically against advanced stage cancer. Given the broad range of expression levels observed in the recently defined tumor antigen EphA2 in a diverse types of cancers, especially in advanced stage or metastatic cancers, the authors evaluated the effectiveness of vaccination using DCs pulsed with EphA2-derived peptides (Eph-DCs) in a murine colon cancer model. METHODS: EphA2 protein expression levels were evaluated in advanced colorectal carcinoma tissues from 10 patients by Western blot analysis. C57BL/6 mice were immunized with Eph-DCs twice weekly. Interferon gamma (IFN-gamma) ELISPOT assays were used for the analysis of CD8-positive T cells that were specific for EphA2-derived peptide. Immunized mice were challenged subcutaneously with EphA2-positive murine colorectal adenocarcinoma (MC38) mouse colon tumors or with EphA2-negative BL6 melanoma tumors. In some experiments, mice were injected with anti-CD8, anti-CD4, or antiasialo GM1 antibody to deplete corresponding lymphocyte subsets. RESULTS: Among 10 samples of advanced colorectal carcinoma, 6 samples (60%) overexpressed EphA2. IFN-gamma ELISPOT assays revealed that EphA2-derived peptide-specific CD8-positive T cells were generated by immunization with Eph-DCs. Immunization with Eph-DCs inhibited MC38 tumor growth compared with immunization using unpulsed DCs or phosphate-buffered saline. In contrast, Eph-DC vaccination had no effect on BL6 growth. Antibody depletion studies revealed that both CD8-positive T cells and CD4-positive T cells, but not natural killer cells, played critical roles in the efficacy observed for immunizations with Eph-DCs. Eph-DC vaccines resulted in long-term antitumor immunity against a rechallenge with MC38 tumor cells. CONCLUSIONS: The current results demonstrated that Eph-DC vaccines may represent a promising preventative/therapeutic modality in the cancer setting.  相似文献   

20.
乳腺癌干细胞是导致乳腺癌复发、转移和耐药的根源之一。microRNA(miRNAs)是一类小分子非编码RNA,可与靶mRNA的3’UTR区域结合而导致该mRNA分子的翻译受到抑制,参与多种生物功能的调节。最近研究发现,miRNAs参与乳腺癌干细胞的分化、自我更新等生物学特性的调控。MiRNAs可以作为乳腺癌干细胞研究的一个新的切入点。本文就近年来该方面的研究进展做简要综述。  相似文献   

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