Fusion hybrid of dendritic cells and engineered tumor cells expressing interleukin-12 induces type 1 immune responses against tumor

AIMS AND BACKGROUND: Dendritic cell (DC)-tumor fusion hybrid vaccinees that facilitate antigen presentation represent a novel powerful strategy in cancer immunotherapy. Preclinical studies have demonstrated that IL-12 promotes specific antitumor immunity mediated by T cells in several types of tumors. In the present study, we investigated the antitumor immunity derived from vaccination of fusion hybrids between DCs and engineered J558/IL-12 myeloma cells secreting Th1 cytokine IL-12. METHODS: The expression vector pcDNA-IL-12 was generated and transfected into J558 myeloma cells and then bone marrow-derived DCs were fused with engineered J558/IL-12 cells. The antitumor immunity derived from vaccination of the fusion hybrid DC/J558/IL-12 was evaluated in vitro and in vivo. RESULTS: DC/J558/IL-12 cells secreted recombinant IL-12 (1.6 ng/mL), and inoculation of BALB/c mice with DC/J558/IL-12 hybrid induced a Th1 dominant immune response and resulted in tumor regression. Immunization of mice with engineered DC/J558/IL-12 hybrid elicited stronger J558 tumor-specific cytotoxic T lymphocyte (CTL) responses in vitro as well as more potent protective immunity against J558 tumor challenge in vivo than immunization with the mixture of DCs and J558/IL-12, J558/IL-12 and J558, respectively. Furthermore, the anti-tumor immunity mediated by DC/J558/IL-12 tumor cell vaccination in vivo appeared to be dependent on CD8+ CTL. CONCLUSIONS: These results demonstrate that the engineered fusion hybrid vaccines that combine Th1 cytokine gene-modified tumor cells with DCs may be an attractive strategy for cancer immunotherapy.     

Strategies for antigen loading of dendritic cells to enhance the antitumor immune response

Dendritic cells (DCs) primed with tumor antigens can effectively mediate the regression of a variety of established solid malignancies in both murine and human models. Despite such clinical efficacy, the optimal means of DC priming is unknown. The goal of this study was to compare three methods of tumor preparation: irradiation, boiling, or freeze thaw lysis for DC priming. Mouse bone marrow-derived DCs were loaded with defined ratios of E.G7 tumor cells expressing a model tumor antigen, OVA. Sensitized DCs were used for stimulation of OVA-specific CTLs derived from OT-1 T-cell receptor transgenic mice. IFN-gamma release, determined by ELISA at 24 and 48 h, was used to assess the expression of antigens by DCs. DCs loaded with irradiated tumors were effective stimulators for OT-1 CTLs, whereas DCs stimulated with freeze-thawed or boiled tumors did not stimulate IFN-gamma production. Freeze-thaw lysis appeared to inhibit CTL activity in vitro and in two of three cases, this effect was not overcome by the addition of OVA. The ability to load irradiated tumor cells was reproduced in two analogous human melanoma models using melanoma cell lines expressing gp100 and CTL clones specific for a gp100 melanoma antigen. Consistent with the in vitro data, only DC/irradiated tumor vaccines were effective in preventing or delaying outgrowth of E.G7 and a poorly immunogenic murine squamous cell carcinoma (SCCVII), on local tumor challenge. These data demonstrate that the method of tumor cell preparation clearly influences the ability of DCs to present antigen to T cells. Correlation of in vitro data with the generation of protective immunity in vivo suggests the utility of irradiated tumor-primed DCs as a means to generate protective immunity in patients with solid malignancies.     

Targeting the tumor microenvironment to enhance antitumor immune responses

The identification of tumor-specific antigens and the immune responses directed against them has instigated the development of therapies to enhance antitumor immune responses. Most of these cancer immunotherapies are administered systemically rather than directly to tumors. Nonetheless, numerous studies have demonstrated that intratumoral therapy is an attractive approach, both for immunization and immunomodulation purposes. Injection, recruitment and/or activation of antigen-presenting cells in the tumor nest have been extensively studied as strategies to cross-prime immune responses. Moreover, delivery of stimulatory cytokines, blockade of inhibitory cytokines and immune checkpoint blockade have been explored to restore immunological fitness at the tumor site. These tumor-targeted therapies have the potential to induce systemic immunity without the toxicity that is often associated with systemic treatments. We review the most promising intratumoral immunotherapies, how these affect systemic antitumor immunity such that disseminated tumor cells are eliminated, and which approaches have been proven successful in animal models and patients.     

Tumour cells engineered to secrete interleukin-15 augment anti-tumour immune responses in vivo.

We examined the effect of interleukin-15 (IL-15) gene transfer into tumour cells on the host's anti-tumour response. In BALB/c mice IL-15 producing Meth-A cells (Meth-A/IL-15) underwent complete rejection, in a response characterized by massive infiltration of CD4+ T-cells and neutrophils. In contrast, Meth-A cells transfected with vector alone (Meth-A/Neo) grew rapidly. Moreover, rechallenged parental cells also were rejected in association with CD8* T-cell infiltration. However, in nude mice there was no drastic difference between Meth-A/IL-15 and Meth-A/Neo cells. These results demonstrate that IL-15-secreting tumour cells can stimulate local and systemic T-cell-dependent immunity and therefore may have a potential role in cancer therapy.     

Dendritic cells fused with mastocytoma cells elicit therapeutic antitumor immunity

Characterization of the spontaneous immune response that frequently occurs in tumor-bearing animals, as well as immunization using dendritic cells pulsed with tumor antigens, suggests that a limiting factor of the tumor-specific immune response may be a defect in the co-stimulatory signal that is required for optimal activation of T cells. In this work, we describe a new approach to improve the antigen-presenting capacity of tumor cells, which does not require a source of purified tumor-associated antigen. We fused P815 mastocytoma cells with bone marrow-derived dendritic cells. We obtained one hybrid that displayed the phenotypic and functional properties of dendritic cells and expressed mRNA coding for the tumor-associated antigen P815 A/B. Injections of irradiated hybrid cells prevented the growth of pre-implanted mastocytoma and induced long-lasting tumor resistance. Int. J. Cancer76:250–258, 1998.© 1998 Wiley-Liss, Inc.     

Local administration of IL-12-transfected dendritic cells induces antitumor immune responses to colon adenocarcinoma in the liver in mice

Colorectal cancer is one of the most common fatal malignancies in the United States, with an incidence second only to lung cancer. The liver is the most common site of colorectal metastases and frequently the only affected organ once the primary tumor has been surgically removed. The only potentially curative treatment for metastatic colorectal cancer in the liver is surgery, although most patients are not eligible for resection. We have therefore, evaluated the therapeutic efficacy of dendritic cells (DCs) engineered to express IL-12 in a liver metastasis model. Direct administration of DCs into the portal vein significantly inhibited the growth of established MC38 colon carcinoma in the liver in C57BL/6 mice. This effect was accompanied by an intratumoral accumulation of CD4+, CD8+, and NLDC-145+ immune effector cells, and also resulted in a systemic immune response as determined by enhanced production of IFN-gamma by T lymphocytes isolated from both spleen and draining lymph nodes. Evaluation of homing of Cy3-labeled DCs following the portal vein injection confirmed their distribution in the liver and lymphoid tissue. Thus, a local delivery of DCs transduced with the IL-12 gene can not only inhibit colorectal tumor growth in vivo but also mount systemic antitumor immune responses. This approach is likely to improve the outcome of immunotherapy for metastatic colorectal cancer since high numbers of tumor-associated DCs positively correlate with a more favorable prognosis. Simultaneous local gene therapy with IL-12 will further improve clinical efficacy without placing the patient at risk for systemic toxicity.     

Route of administration influences the antitumor effects of bone marrow-derived dendritic cells engineered to produce interleukin-12 in a metastatic mouse prostate cancer model

Gene-modified dendritic cells (DC) provide unique therapeutic strategies for prostate cancer; however, the comparative evaluation of specific delivery options using appropriate preclinical models has not been described. In this study, bone marrow-derived DC were genetically engineered to express high levels of interleukin-12 (IL-12) with or without the costimulatory molecule B7-1, by ex vivo infection with recombinant adenoviral vectors. We used an orthotopic metastatic mouse prostate cancer preclinical model (178-2 BMA) to compare two therapeutic protocols for DC delivery, in situ and subcutaneous. DC were generated from bone marrow of syngeneic 129/Sv mice by culturing in the presence of GM-CSF and IL-4. In vitro DC/IL-12 or DC/IL-12/B7 produced high levels of biologically active IL-12. In situ delivery of DC/IL-12 or DC/IL-12/B7 induced a significant suppression of primary tumor growth compared to DC/beta gal controls (P=.0328 and P=.0019, respectively), as well as reduced numbers of spontaneous lung metastatic nodules (P=.1404 and P=.0335, respectively). In survival experiments, in situ DC/IL-12 injection demonstrated a small but statistically significant advantage (P=.0041). Subcutaneous, tumor lysate pulsed DC/IL-12 significantly decreased tumor size (P=.0152) and increased survival (P=0.0433) compared to HBSS controls but the decrease in the number of spontaneous lung metastases did not achieve statistical significance. Both in situ and subcutaneous treatments enhanced cytolytic activities of natural killer (NK) cells and cytotoxic T lymphocytes (CTL). In this preclinical model, gene-modified DC-based intratumoral immunotherapy was shown to be an effective therapeutic strategy for locally advanced prostate cancer based on tumor growth suppression, inhibition of metastasis and survival improvement.     

Dendritic cells genetically engineered to simultaneously express endogenous tumor antigen and granulocyte macrophage colony-stimulating factor elicit potent therapeutic antitumor immunity.

Recently, several studies have shown that vaccine therapy using dendritic cells (DCs) genetically engineered to express a surrogate tumor antigen can effectively induce antitumor immunity. In this study, murine bone marrow DCs were adenovirally transduced with murine endogenous tumor antigen gp70 expressed in CT26 cells and granulocyte macrophage colony-stimulating factor (GM-CSF), and we examined whether antigen-specific CTL responses and therapeutic immunity could be induced in mice immunized with those genetically modified DCs. The cytotoxic activity against CT26 in mice immunized with gp70-transduced DCs was significantly higher than that in control (P < 0.01) and was enhanced by GM-CSF-cotransduction (P < 0.001). GM-CSF gene transfer into DCs expressing tumor-associated antigen enhances CC chemokine receptor 7 expression on DCs, leading to improved migratory capacity of DCs to draining lymph nodes. Consequently, an effective antitumor immune response would be induced. Vaccination using gp70-transduced DCs provided remarkable therapeutic efficacy in s.c. models. Moreover, it could be sufficiently augmented by GM-CSF-cotransduction of DCs. These results support that vaccination therapy using DCs simultaneously transduced with tumor-associated antigen can elicit potent CTL response, and GM-CSF-cotransduction of DCs could optimize therapeutic response. Further investigation is needed to optimize this vaccine therapy to achieve the obvious benefit in clinical application.     

Selective targeting of antitumor immune responses with engineered live-attenuated Listeria monocytogenes

Improved immunization and ex vivo T-cell culture strategies can generate larger numbers and more potent tumor-specific effector cells than previously possible. Nonetheless, the capacity of these cells to eliminate established tumors is limited by their ability to efficiently enter tumor-bearing organs and mediate their effector function. In the current study, we show that the administration of an engineered organ-homing microbe selectively targets tumor-specific immune responses to metastases within that organ. Specifically, an attenuated Listeria monocytogenes strain, which preferentially infects the liver following systemic administration, dramatically enhances the activity of a cancer vaccine against liver metastases but not metastases in the lung. This enhanced activity results from both local recruitment of innate immune effectors as well as concentration and increased activation of vaccine-induced antitumor T cells within the liver. These findings show a general approach to focus systemic cancer immunotherapies to specific organs bearing tumor metastases by taking advantage of differential tropisms and the proinflammatory nature of microbes.     

β‐glucan restores tumor‐educated dendritic cell maturation to enhance antitumor immune responses

Tumors can induce the generation and accumulation of immunosuppressive cells such as myeloid‐derived suppressor cells (MDSCs) in a tumor microenvironment, contributing to tumor escape from immunological attack. Although dendritic cell‐based cancer vaccines can initiate antitumor immune responses, tumor‐educated dendritic cells (TEDCs) involved in the tolerance induction have attracted much attention recently. In this study, we investigated the effect of β‐glucan on TEDCs and found that β‐glucan treatment could promote the maturation and migration of TEDCs and that the suppressive function of TEDCs was significantly decreased. Treatment with β‐glucan drastically decreased the levels of regulatory T (Treg) cells but increased the infiltration of macrophages, granulocytes and DCs in tumor masses, thus elicited Th1 differentiation and cytotoxic T‐lymphocyte responses and led to a delay in tumor progression. These findings reveal that β‐glucan can inhibit the regulatory function of TEDCs, therefore revealing a novel function for β‐glucan in immunotherapy and suggesting its potential clinical benefit. β‐Glucan directly abrogated tumor‐educated dendritic cells‐associated immune suppression, promoted Th1 differentiation and cytotoxic T‐lymphocyte priming and improved antitumor responses.     

Intratumoral injection of dendritic cells engineered to secrete interleukin-12 by recombinant adenovirus in patients with metastatic gastrointestinal carcinomas.

PURPOSE: To evaluate the feasibility and safety of intratumoral injection of autologous dendritic cells (DCs) transfected with an adenovirus encoding interleukin-12 genes (AFIL-12) for patients with metastatic gastrointestinal carcinomas. Secondarily, we have evaluated biologic effects and antitumoral activity. PATIENTS AND METHODS: Seventeen patients with metastatic pancreatic (n = 3), colorectal (n = 5), or primary liver (n = 9) malignancies entered the study. DCs were generated from CD14+ monocytes from leukapheresis, cultured and transfected with AFIL-12 before administration. Doses from 10 x 10(6) to 50 x 10(6) cells were escalated in three cohorts of patients. Patients received up to three doses at 21-day intervals. RESULTS: Fifteen (88%) and 11 of 17 (65%) patients were assessable for toxicity and response, respectively. Intratumoral DC injections were mainly guided by ultrasound. Treatment was well tolerated. The most common side effects were lymphopenia, fever, and malaise. Interferon gamma and interleukin-6 serum concentrations were increased in 15 patients after each treatment, as well as peripheral blood natural killer activity in five patients. DC transfected with AFIL-12 stimulated a potent antibody response against adenoviral capsides. DC treatment induced a marked increase of infiltrating CD8+ T lymphocytes in three of 11 tumor biopsies analyzed. A partial response was observed in one patient with pancreatic carcinoma. Stable disease was observed in two patients and progression in eight patients, with two of the cases fast-progressing during treatment. CONCLUSION: Intratumoral injection of DC transfected with an adenovirus encoding interleukin-12 to patients with metastatic gastrointestinal malignancies is feasible and well tolerated. Further studies are necessary to define and increase clinical efficacy.     

Synthetic CD4+ T cell-targeted antigen-presenting cells elicit protective antitumor responses

CD4(+) helper T cells are critical for protective immune responses and yet suboptimally primed in response to tumors. Cell-based vaccination strategies are under evaluation in clinical trials but limited by the need to derive antigen-presenting cells (APC) from patients or compatible healthy donors. To overcome these limitations, we developed CD4(+) T cell-targeted synthetic microbead-based artificial APC (aAPC) and used them to activate CD4(+) T lymphocytes specific for a tumor-associated model antigen (Ag) directly from the naive repertoire. In vitro, aAPC specifically primed Ag-specific CD4(+) T cells that were activated to express high levels of CD44, produced mainly interleukin 2, and could differentiate into Th1-like or Th2-like cells in combination with polarizing cytokines. I.v. administration of aAPC led to Ag-specific CD4(+) T-cell activation and proliferation in secondary lymphoid organs, conferred partial protection against subcutaneous tumors, and prevented the establishment of lung metastasis. Taken together, our data support the use of cell-free, synthetic aAPC as a specific and versatile alternative to expand peptide-specific CD4(+) T cells in adoptive and active immunotherapy.     

Melanoma-infiltrating dendritic cells induce protective antitumor responses mediated by T cells

Dendritic cells are the most potent antigen-presenting cells inducing innate and adaptive immune response. Dendritic cells infiltrate melanomas, but their ability to induce host antitumor immunity remains obscure. In a previous study, we have observed that melanoma-infiltrating dendritic cells have the capacity to process antigens and migrate to lymph nodes to prime T lymphocytes. Here, we observed that melanoma-infiltrating dendritic cells extracted from melanoma without any additional manipulations were able to protect naive mice against a lethal challenge with the tumor. Remarkably, this was achieved with reinjection of 10(5) melanoma-infiltrating dendritic cells, a number that did not exceed the total number of melanoma-infiltrating dendritic cells recovered from one single tumor. Three observations indicate that protection was due to the natural loading of melanoma-infiltrating dendritic cells with tumor antigens. First, the protective effect was not observed with equivalent numbers of bone marrow-derived dendritic cells. Second, the protection induced was specific for the tumor from which the tumor-infiltrating dendritic cells were isolated. Third, depletion experiments indicate that both CD4+ and CD8+ T lymphocytes were required during the effector phase of the antitumor response. Hence, designing strategies aimed at rendering melanoma-infiltrating dendritic cells visible to host T cells may boost spontaneous antitumor immunity.     

Characterization of antitumor immunization to a defined melanoma antigen using genetically engineered murine dendritic cells

A murine model of dendritic cell (DC)-based genetic immunization to a defined human melanoma antigen (Ag), MART-1/Melan-A (MART-1), was developed. The MART-1 gene was stably transfected into the nonimmunogenic mouse fibrosarcoma cell line NFSA that is syngeneic in C3Hf/Sem/Kam (C3H, H-2k) mice to generate the NFSA(MART1) cell line. In vivo protection from a lethal NFSA(MART1) tumor challenge could be generated by DCs transduced with a recombinant adenovirus (AdV) vector expressing MART-1 (AdVMART1). This model has the following characteristics: (a) immunological specificity and memory, (b) comparable protection for varying transduction multiplicities of infection, cell doses, and sites of DC inoculation but, interestingly, worse protection with increasing numbers of vaccinations, (c) the ability to treat small established tumors, (d) an absolute requirement for CD8 and CD4 T cells, (e) generation of MART-1-specific splenic cytotoxic T lymphocytes, and (f) up-regulation of both T helper type 1 and T helper type 2 cytokines. Genetically engineered DCs presenting defined tumor Ags represent an attractive method to generate effective immune responses.     

Similar immune responses and antitumor effects of murine dendritic cells loaded with either exogenous or endogenous-synthesized protein

Conceptually, dendritic cells (DCs) take up and process exogenous antigens that are presented on MHC (major histocompatibility complex) class II molecules to stimulate CD4+ T cells, and present endogenously-produced proteins to CD8+ T cells through an MHC class I-dependent pathway. In this study, we compared the antitumor effects generated in vivo after vaccinations with DCs either loaded with exogenous protein (DCs-exo) or presenting antigens derived from endogenous-synthesized protein (DCs-endo). We used the murine MC26SC31 colon carcinoma cell line expressing on the cell surface the human CD4 (hCD4) molecule as a model tumor-associated antigen (TAA). Bone marrow (BM)-derived DCs-endo were obtained from histocompatible transgenic mice constitutively expressing hCD4; BM-derived DCs-exo were obtained after in vitro loading DCs, from syngenic normal mice, with purified soluble hCD4 protein (shCD4). Altogether, our results show that intravenous (i.v.) administration of DCs-exo and DCs-endo can trigger similar cytotoxic and humoral protecting immune responses against a lethal tumor challenge. hCD4 antigen-specific T cell-mediated cytotoxic immune response was not accompanied by elevated INF-gamma serum levels. This suggests, in the case of DCs-exo, a possible in vivo CTL cross-priming triggering a CD8+ T cell-mediated immune response in the absence of de novo antigen synthesis within the DCs.     

Induction of systemic and therapeutic antitumor immunity using intratumoral injection of dendritic cells genetically modified to express interleukin 12.

Bone marrow-derived dendritic cells (BM-DCs) retrovirally transduced with genes encoding murine interleukin (IL)-12 stably expressed bioactive IL-12 protein at high levels. Intratumoral injection with IL-12 gene-modified BM-DCs resulted in regression of day 7 established weakly immunogenic tumors (MCA205, B16, and D122). This antitumor effect was substantially better than that of IL-12-transduced syngeneic fibroblasts or nontransduced BM-DCs. Furthermore, intratumoral injection with IL-12-transduced dendritic cells (DCs) induced specific TH1-type responses to the tumor in regional lymph nodes and spleen at levels greater than those of IL-12-transduced fibroblasts or nontransduced BM-DCs. Trafficking studies confirmed that intratumorally injected IL-12-transduced DCs, but not fibroblasts, could migrate to the draining lymph node to the same extent as nontransduced BM-DCs. This strategy designed to deliver genetically modified DCs to tumor sites is associated with systemic and therapeutic antitumor immunity and is an alternative approach to those that use delivery of DCs loaded with tumor antigen. These results support the clinical application of IL-12 gene-modified DCs in patients with cancer.     

Vector-based vaccine/cytokine combination therapy to enhance induction of immune responses to a self-antigen and antitumor activity

Many antigens associated with human tumors are overexpressed in tumor cells as compared with normal tissues; these "self" tumor-associated antigens are also expressed during fetal development, and it is, thus, not surprising that they are either weakly immunogenic or functionally nonimmunogenic in the tumor-bearing host. In the studies reported here, we have used different vaccines and vaccine strategies in an attempt to develop antitumor immunity in a stringent animal model. The tumor antigen used was human carcinoembryonic antigen (CEA). The model used was CEA transgenic mice, in which the human CEA transgene is under the control of the endogenous CEA promoter; CEA is expressed in fetal tissues and normal gastrointestinal tissues, and CEA protein is found in sera. Previous studies have shown these CEA transgenic mice to be tolerant to the induction of CEA immunity using CEA protein in adjuvant as an immunogen. CEA-expressing tumor cells were implanted 14 days before vaccine therapy. The vaccines used were recombinant vaccinia virus containing the transgenes for CEA and three T-cell costimulatory molecules [B7-1, ICAM-1, and LFA-3, designated recombinant vaccinia (rV)-CEA/TRICOM], with each transgene under the control of individual poxvirus promoters, and a replication-defective avipox virus (fowlpox; rF) containing the same four transgenes (designated rF-CEA/TRICOM). The results demonstrate that (a) continued boosting with vaccine is required to maintain CEA-specific T-cell responses, and boosting with rF-CEA/TRICOM is superior to boosting with rF-CEA; (b) a diversified vaccination protocol consisting of primary vaccination with rV-CEA/TRICOM followed by boosting with rF-CEA/TRICOM is more efficacious than homogeneous vaccination with rF-CEA/TRICOM in the induction of both CEA-specific T-cell responses and antitumor activity; and (c) the use of cytokines, local granulocyte macrophage colony-stimulating factor (GM-CSF) and low-dose systemic interleukin 2, in combination with vaccine is essential in inducing antitumor activity, as compared with the use of cytokines alone, or the use of vaccines without cytokine. Both GM-CSF and interleukin 2 were shown to contribute to the induction of CEA-specific T-cell responses. These studies thus provide a "proof of concept" that potent vaccines and vaccine strategies, in combination with cytokines, may be essential to obtain the level of T-cell responses directed against a self-antigen that is necessary to achieve antitumor responses.     

骨髓瘤独特型抗原致敏树突细胞诱导的主动免疫反应

背景与目的:大多数多发性骨髓瘤(multiplemyeloma,MM)无法通过大剂量化疗和造血干细胞移植治愈,应用树突细胞(DCs)瘤苗清除MM患者化疗后残留的骨髓瘤细胞,是近年来骨髓瘤免疫疗法的新策略。本研究旨在探讨负载Id的DC独特型瘤苗对自体MM细胞的体外杀伤作用。方法:从MM患者外周血中分离获取DCs前体细胞,用GM鄄CSF与IL鄄4诱导分化,培养第5天加入从患者血清中提取的IgG的F(ab’)2片段(Id),第7天加TNF鄄α促成熟,将Id冲击致敏的DCs与自体T淋巴细胞共培养3天,获得肿瘤特异性细胞毒性T淋巴细胞(CTLs)。MTT法检测致敏DCs促自体T淋巴细胞增殖能力,以及患者CTLs对自体MM细胞的特异性细胞毒杀伤作用。结果:GM鄄CSF、IL鄄4和TNF鄄α联合可以有效地从MM患者外周血单核细胞中诱导出大量成熟的功能性DCs。MM患者自体血清Id冲击致敏的成熟DCs能够显著提高T细胞增殖能力,且与DC∶T的比值呈正相关;同时在1∶10时刺激细胞为负载了Id的成熟DC组刺激指数(SI)值(39.1±6.0)%,明显高于未经Id刺激的成熟DC组、经Id刺激的未成熟DC组以及未经Id刺激的未成熟DC组[(19.3±7.7)%、(15.9±6.1)%和(11.4±4.9)%]。负载了Id的成熟DC能够使幼稚T细胞活化成为肿瘤独特型CTLs,各个剂量的CTLs均能诱导出针对自体MM细胞的抑制性杀伤反应,并且     

CM—CSF及IL—4增强树突状细胞免疫功能

目的 探讨粒／巨噬细胞集落刺激因子（ＧＭ－ＣＳＦ）及白介素－４（ＩＬ－４）对正常成人及大肠癌患者树突状细胞（ＤＣ）表现人白细胞抗原（ＨＬＡ）－ＤＲ及Ｂ７等免疫分子表达及其免疫功能的影响。方法 分离正常成人（ｎ＝１０）及大肠癌患者（ｎ＝１０）外周血ＤＣ,以ＧＭ－ＣＳＦ及ＩＬ－４联合刺激正常成人及大肠癌者ＤＣ,检测ＧＭ－ＣＳＦ及ＩＬ－４联合刺激前后ＤＣ表现ＨＬＡ－ＤＲ及Ｂ７表达水平及ＤＣ免疫功能变化。