TUMOR IMMUNITY GENERATED BY DENDRITIC CELLS

描述（由申请人提供）：我们对人类树突状细胞的理解的进展已经解决了许多关于先天性和适应性免疫的发生以及树突状细胞如何控制这些针对肿瘤抗原的反应的重要未知因素。人类树突状细胞亚型的多样性日益得到认可，也导致了各种树突状细胞功能的更异质，可能更真实的画面。其中一些发现解决了长期存在的未知问题，而另一些则迫使我们重新审视公认模型的准确性。由此产生的问题构成了我们计划研究的基础。我们假设不同的人树突状细胞亚型通过协调NK和NKT细胞的激活，刺激适应性、MHC限制性和抗原特异性T细胞免疫，实现最有效的肿瘤免疫。我们将比较单核细胞来源的树突状细胞与朗格汉斯细胞或由CD 34+祖细胞产生的真皮间质树突状细胞的不同群体，以在以下特定目标中测试树突状细胞诱导的肿瘤免疫的统一概念。目的1确定不同树突状细胞亚型分泌的细胞因子，这些细胞因子对NK、NKT和效应记忆T细胞，特别是CD 8 + CTL的刺激至关重要，重点关注IL-15、IL-7、IL-2和IL-23、IL-12的活性; aim 2将定义成熟而非未成熟树突状细胞激活吲哚胺2，3-双加氧酶的生物学机制，其可以抑制针对肿瘤抗原的免疫应答;并且目的3将确定抗体调理作用是否从末端降解途径中挽救肿瘤抗原，以分别在CD 1d或MHC上呈递给NKT或T细胞。这些研究将为使用树突状细胞亚型（无论是组合使用还是以初免-加强序列使用）来产生先天性和适应性免疫应答以及因此更有效的整体肿瘤免疫确定新的生物学原理。（与公共卫生的相关性/非专业摘要：专门的白色血细胞，称为树突状细胞，是免疫系统的关键刺激因子。树突状细胞包含不同的亚群，在功能上具有潜在的非常有用的差异。这些研究将调查树突状细胞亚群单独和组合可以刺激针对癌症的免疫力的生物学机制，这是一个主要的公共卫生问题。预计将有新的和改进的基于免疫的癌症治疗方法，最有效的应用可能是治疗初级治疗后的微小残留疾病。

DESCRIPTION (provided by applicant): Advances in our understanding of human dendritic cells have resolved many important unknowns about the onset of innate and adaptive immunity and how dendritic cells can control these responses against tumor antigens. The increasingly recognized diversity of human dendritic cell subtypes has also led to a more heterogeneous, and probably more realistic picture of various dendritic cell functions. Some of these findings solve longstanding unknowns, while others compel us to reexamine the accuracy of accepted models. The resulting questions comprise the basis of our planned studies. We hypothesize that distinct human dendritic cell subtypes achieve the most effective tumor immunity by coordinating the activation of NK and NKT cells, with the stimulation of adaptive, MHC-restricted and antigen-specific T cell immunity. We will compare distinct populations of monocyte-derived dendritic cells with Langerhans cells or dermal-interstitial dendritic cells generated from CD34+ progenitors to test this unifying concept of dendritic cell-induced tumor immunity in the following specific aims. Aim 1 will determine the cytokines secreted by different dendritic cell subtypes that are critical to the stimulation of NK, NKT, and effector memory T cells, especially CD8+ CTL, focusing on the activity of IL-15 vs IL-7 vs IL-2, and IL-23 vs IL-12; Aim2 will define the biologic mechanism(s) by which mature, rather than immature dendritic cells activate indoleamine 2,3-dioxygenase, which can suppress the immune response against tumor antigens; and Aim 3 will establish whether antibody-opsonization salvages tumor antigen from the terminally degradative pathway for presentation on CD1d or MHC to NKT or T cells respectively. These studies will define new biologic rationales for the use of dendritic cell subtypes, either in combination or in a prime-boost sequence, to generate both innate and adaptive immune responses and hence more effective overall tumor immunity. (Relevance to Public Health / Lay Summary: Specialized white blood cells, called dendritic cells, are key stimulators of the immune system. Dendritic cells comprise different subsets with potentially very useful differences in function. These studies will investigate the biologic mechanisms by which dendritic cell subsets alone and in combination can stimulate immunity against cancer, which is a major public health problem. New and improved approaches for the immune-based treatment of cancer are anticipated, with the most effective application likely being the treatment of minimal residual disease after primary therapy.)