TUMOR IMMUNITY GENERATED BY DENDRITIC CELLS

描述(申请人提供)：我们对人类树突状细胞的了解的进步已经解决了许多关于先天免疫和获得性免疫的开始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数。人类树突状细胞亚型的日益多样化也导致了对各种树突状细胞功能的更多异质性，可能也更真实。其中一些发现解决了长期未知的问题，而另一些发现则迫使我们重新审视已被接受的模型的准确性。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，以及适应性、MHC限制性和抗原特异性T细胞免疫的刺激，实现最有效的肿瘤免疫。我们将比较不同群体的单核细胞来源的树突状细胞与朗格汉斯细胞或由CD34+祖细胞产生的真皮间质树突状细胞，以测试树突状细胞诱导肿瘤免疫这一统一概念的以下特定目的。目的1将确定不同树突状细胞亚型分泌的细胞因子对NK、NKT和效应记忆T细胞，尤其是CD8+CTL的刺激至关重要，重点是IL-15、IL-7和IL-2、IL-23和IL-12的活性；AIM2将确定成熟的而不是未成熟的树突状细胞激活吲哚胺2，3-双加氧酶的生物学机制(S)，该酶可以抑制针对肿瘤抗原的免疫反应；以及目的3将确定抗体调理是否将肿瘤抗原从CD1d或MHC的末端降解途径挽救到NKT或T细胞。这些研究将为使用树突状细胞亚型确定新的生物学原理，无论是组合使用还是在主增强序列中使用，以产生先天和获得性免疫反应，从而更有效地整体肿瘤免疫。与公共卫生/生活相关概述：称为树突状细胞的特殊白血球是免疫系统的关键刺激因子。树突状细胞由不同的亚群组成，在功能上具有潜在的非常有用的差异。这些研究将探索树突状细胞亚群单独和联合使用可以刺激对癌症的免疫的生物机制，这是一个主要的公共卫生问题。以免疫为基础的癌症治疗的新的和改进的方法是预期的，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.)