IMMUNITY TO MELANOMA VIA DENDRITIC CELLS

摘要：人类肿瘤免疫学已经通过抗原和相应的肿瘤特异性淋巴细胞，特别是杀伤和辅助t细胞的鉴定而得到了进展。该项目将利用树突状细胞（DC）增强黑色素瘤抗原对t细胞的呈递，主要用于人类，也用于小鼠模型。我们的动力有三个方面：(1)dc可以从不同的前体种群中大量体外产生；(2) dc上的MHC I类和II类产物可以通过喂养凋亡和坏死细胞而携带一系列肿瘤抗原；(3)携带抗原的树突状细胞能快速增强人体的原位免疫系统。因此，达拉斯和纽约的一个综合项目可以开始对患者进行黑色素瘤抗原的主动免疫，并结合实验室研究，了解如何增强肿瘤抗原的DC加工，评估不同DC亚群和成熟状态的作用，并观察DC在肿瘤和原位淋巴结中的功能。这个项目强调黑色素瘤，因为已知肿瘤特异性t细胞存在于小鼠和人类中，现在很明显，dc可以在体外呈现来自凋亡细胞的黑色素瘤抗原。人类肿瘤特异性免疫的记录已经变得更容易获得，定量分析已经到位，包括：mhc四聚体的结合，elispot的生产和召回试验，以引发特异性杀伤t细胞。该项目将包括两个双中心随机试验。在第一篇文章中，我们将比较两种类型的DC在引发对黑色素瘤肽的免疫方面的作用，并寻找对其他抗原的免疫反应的扩散，作为体内交叉呈现的指标。在第二部分，我们将比较装载多肽的dc与垂死的肿瘤细胞在扩增肿瘤特异性CD4和CD8 t细胞方面的差异。用于管理、DC生产和免疫监控的共享核心设施将激励和标准化交互。总之，我们假设dc，自然的辅助剂，将增强对肿瘤抗原的免疫，从而可以追求癌症疫苗接种和治疗的临床结果。合作机构：亚利桑那癌症中心，图森，亚利桑那贝勒研究所，达拉斯，德克萨斯州居里研究所，巴黎，法国纽约纪念斯隆凯特琳癌症中心，纽约德克萨斯大学，西南医学中心，达拉斯，德克萨斯州。

Revised Abstract: Human tumor immunology has been advanced by the identification of antigens and the corresponding tumor specific lymphocytes, particularly killer and helper T-cells. This program will exploit the dendritic cell [DC] to enhance presentation of melanoma antigens to T-cells, primarily in humans but also in mouse models. Our impetus is 3 fold: (1) DCs can be generated in large numbers ex vivo from different precursor populations; (2) MHC class I and II products on DCs can be charged with an array of tumor antigens by feeding apoptotic and necrotic cells; (3) antigen-bearing DCs can rapidly boost the human immune system in situ. Therefore an integrated program in Dallas and New York can begin to actively immunize patients to melanoma antigens, concommitant with laboratory studies to learn to enhance DC processing of tumor antigens, to evaluate the roles of distinct DC subsets and maturation states, and to observe DC function in tumors and lymph nodes in situ. This program emphasizes melanoma, because tumor-specific T-cells are known for mice and humans, and it is now evident that DCs can present in vitro melanoma antigens derived from apoptotic cells. Documentation of tumor-specific immunity in humans has become more accessible with quantitative assays that are in place and include: binding of MHC-tetramers, production of ELISPOTS, and recall assays to elicit specific killer T-cells. The program will include two dual center randomized trials. In the first we will compare two types of DC in eliciting immunity to melanoma peptides, and look for spreading of the immune response to other antigens, as an index of cross presentation in vivo. In the second, we will compare DCs loaded with peptides vs. dying tumor cells in expanding tumor specific CD4 and CD8 T-cells. Shared ongoing core facilities for administration, DC production, and immune monitoring will energize and standardize interactions. Together, we hypothesize that DCs, nature's adjuvant, will enhance immunity to tumor antigens so that the clinical consequences for cancer vaccination and therapy can be pursued. COLLABORATING INSTITUTION(S) Arizona Cancer Center, Tucson, Arizona Baylor Research Institute, Dallas, Texas Institute Curie, Paris, France Memorial Sloan Kettering Cancer Center, New York, New York University of Texas, Southwestern Medical Center, Dallas, Texas.