The Significance of MARCO Expression by Tumor-Pulsed Dendritic Cells

肿瘤脉冲树突状细胞表达 MARCO 的意义

• 批准号: 7741683
• 负责人: JAMES J. MULE
• 金额: $ 37.58万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-08-01 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7741683
• 关键词: Address; Adoptive Immunotherapy; Affect; Animals; Antigen Presentation; Antigen-Presenting Cells; Antigens; Back; Binding; Biological Assay; Biology; Bone Marrow Cells; C57BL/6 Mouse; CD8B1 gene; Cancer Vaccines; Cell Adhesion; Cell Separation; Cell physiology; Cell surface; Cells; Cellular biology; Clinical; Clinical Protocols; Clinical Trials; Data; Dendritic Cell Vaccine; Dendritic Cells; Dose; Equine mule; Expressed Sequence Tags; Family; Funding; Gene Expression; Genes; Grant; Histologic; Human; Immune; Immune response; Immunity; Immunization; Immunotherapeutic agent; In Vitro; Intention; Interleukin-2; Label; Laboratories; Lung; Lymphoid Tissue; Malignant Neoplasms; Measures; Mediating; Modeling; Mus; Nature; Neoplasm Metastasis; Oligonucleotide Microarrays; Patients; Pattern; Phagocytosis; Physiologic pulse; Play; Principal Investigator; Process; Proteins; Recombinant Cytokines; Reporting; Research; Residual state; Role; SR-A proteins; Specificity; Staging; Structure; T-Cell Activation; T-Lymphocyte; Therapeutic; Therapeutic Studies; Time; Transcript; Transgenic Mice; Translations; Treatment Efficacy; Tumor Immunity; Vaccines; Work; advanced disease; base; chemokine; chemokine receptor; cytokine; design; experience; immune function; improved; in vitro Assay; in vivo; macrophage; melanoma; member; migration; novel; pre-clinical; pre-clinical research; programs; receptor; research study; trafficking; tumor; uptake

We reported previously that murine tumor lysate-pulsed dendritic cells (TP-DC) could elicit tumor-specific CD4+ and CD8+ T cell reactivities in vitro and in vivo. TP-DC treatments could result in regression of well- established s.c. and lung metastases, which could be further enhanced by the systemic administration of low-dose IL-2. Although vaccine studies involving TP-DC have been performed, little, if any, information is available on the effects of phagocytic uptake of tumor lysate on DC biology and function. We have investigated gene expression pattern differences between unpulsed DC and TP-DC, using Affymetrix MG- U74Av2 oligonucleotide arrays, which contain ~12,000 genes and ESTs (expressed sequence tags). Upon 24 hr tumor lysate pulsing, the levels of 87 transcripts increased at least threefold while the levels of 121 transcripts were reduced by one-third or more, with accompanying p-values <0.01. Most of these genes encoded a repertoire of proteins important for DC effector functions including cytokines, chemokines and receptors, as well as antigen presentation, cell adhesion, and T cell activation molecules. Interestingly, we observed a high level of expression of a novel member of the class A scavenger receptor family, MARCO on both mouse and human DC. MARCO is thought to play an important role in the immune response by mediating binding and phagocytosis, but also in the formation of lamellipodia-like structures and of dendritic processes. We propose to to define the biology and potential therapeutic implication of TP-DC expressed MARCO. We hypothesize that modulation of MARCO expression will have substantial effects on TP-DC biology and function in vitro and in vivo. We propose the following Specific Aims: 1. To determine the effect of MARCO expression modulation on TP-DC function in vitro; 2. To determine the effect of MARCO expression modulation on TP-DC trafficking in vivo; 3. To determine the therapeutic efficacy of MARCO expression-modulated TP-DC on antitumor activity in mice. The experimental studies outlined in this renewal application are designed to continue our successful preclinical efforts to generate immunization strategies against cancer based on antigen-presenting DC. The findings could have significant translation to human clinical DC vaccine trials.

我们先前报道，小鼠肿瘤裂解物致敏的树突状细胞(TP-DC)可以诱导肿瘤特异性 CD4+和CD8+T细胞在体外和体内的反应性。TP-DC治疗可导致油井的消退。 成立S.C.和肺转移，这可以通过系统地给药进一步加强 小剂量IL-2。尽管已经进行了涉及TP-DC的疫苗研究，但几乎没有任何信息 可用于吞噬摄取肿瘤裂解物对DC生物学和功能的影响。我们有 应用Affymetrix MG-1研究未冲击DC和TP-DC的基因表达谱差异 U74Av2寡核苷酸阵列，包含约12,000个基因和EST(表达序列标签)。vt.在.的基础上 24小时的肿瘤裂解液脉冲，87个转录本的水平至少增加了3倍，而121个转录本的水平 成绩单减少了三分之一或更多，伴随着p值&lt；0.01。大多数这些基因 编码一系列对DC效应功能重要的蛋白质，包括细胞因子、趋化因子和 受体，以及抗原提呈、细胞黏附和T细胞激活分子。有趣的是，我们 观察到A类清道夫受体家族的一个新成员Marco on的高水平表达 无论是小鼠还是人类DC。马可被认为在免疫反应中发挥着重要作用， 介导结合和吞噬作用，也参与片状脂膜结构和树突状细胞的形成 流程。我们建议定义表达的TP-DC的生物学和潜在的治疗意义 马可。我们假设Marco表达的调节将对TP-DC产生实质性的影响 体外和体内的生物学和功能。我们提出了以下具体目标：1.确定效果 Marco在体外对TP-DC功能的调控；2.检测Marco对TP-DC功能的影响 MARCO对TP-DC体内转运的表达调控；3.确定MARCO的治疗效果 表达调控的TP-DC对小鼠抗肿瘤活性的影响。本次更新中概述的实验研究 应用程序旨在继续我们成功的临床前工作，以生成免疫策略 基于抗原递呈DC的抗癌作用。这些发现可能会对人类产生重大影响 DC疫苗临床试验。