Activating robust immunity to tumor-associated antigens:mechanisms and biology

描述（由申请人提供）：治疗性癌症疫苗旨在驱动免疫系统的特异性激活，以治疗现有的恶性肿瘤或预防其复发。由于肿瘤预先存在的免疫抑制机制，这需要强有力的疫苗接种策略。从理论上讲，用凋亡的自体肿瘤细胞接种疫苗是一种特别有前途的方法，可以靶向最多数量的潜在抗原，而无需对其进行单独鉴定。然而，凋亡细胞的感知和清除通常被认为是一个非炎症甚至耐受的过程。主流观点认为，由正常组织转换产生的凋亡细胞被迁移到局部淋巴结的树突状细胞（dc）捕获，在那里它们诱导T细胞耐受、T细胞能量或T细胞缺失，以维持组织稳态并防止宿主的自身免疫。我们最近发现了一种新的DC亚群（nDC），与其他交叉呈递和交叉耐受的DC亚群不同，它在摄取凋亡物质后有效地（交叉）将CD4+和CD8+T细胞引到细胞相关抗原上。nDC的有效佐剂活性很大程度上依赖于它们与凋亡细胞相互作用后产生I型IFN。与其他DC亚群启动的T细胞相比，nDC启动的T细胞显示出更大的原代扩增、细胞因子产生和记忆形成的能力。因此，当暴露于凋亡的肿瘤细胞时，这些nDC在疫苗接种和治疗环境中都能极有效地诱导保护性抗肿瘤反应。我们提出的研究的中心假设是，暴露于凋亡细胞的nDC产生I型IFN对于nDC功能及其随后启动对细胞相关抗原的保护性T细胞反应至关重要。这项工作的长期目标有两个方面：(1)定义dc在细胞死亡后平衡促炎性和抗炎性免疫反应的分子和细胞机制；(2)转化利用这些机制的见解，以设计有效的治疗和预防癌症疫苗。

DESCRIPTION (provided by applicant): Therapeutic cancer vaccines are intended to drive specific activation of the immune system for therapy of existing malignancies or prevention of their recurrence. This requires powerful vaccination strategies, due to the preexisting immunosuppressive mechanisms orchestrated by the tumor. Theoretically, vaccination with apoptotic autologous tumor cells represents a particularly promising way to target the greatest number of potential antigens without the need for their individual identification. However, the sensing and clearance of apoptotic cells is generally considered to be a non-inflammatory or even tolerizing process. The prevailing view has been that apoptotic cells generated by normal tissue turnover are captured by dendritic cells (DCs) that migrate to local lymph nodes, where they induce T cell tolerance, T cell anergy, or T cell deletion in order to maintain tissue homeostasis and prevent autoimmunity in the host. We recently identified a novel DC subset (nDC), that, in contrast with other cross-presenting and cross-tolerizing DC subsets, potently (cross-)primes both CD4+ and CD8+T cells to cell-associated antigens after uptake of apoptotic material. The potent adjuvant activity of the nDC is largely dependent on their production of type I IFN after interacting with apoptotic cells. T cells primed by nDC display a greater capacity for primary expansion, cytokine production, and memory formation on a per cell basis than those primed by other DC subsets. As a consequence, these nDC are extremely potent in the induction of protective anti- tumor responses in both vaccination and therapeutic settings when exposed to apoptotic tumor cells. The central hypothesis underlying our proposed studies is that type I IFN production by nDC exposed to apoptotic cells is critical for nDC function and their subsequent priming of protective T cell responses to cell-associated antigens. The long-term goals of this work are two-fold: (1) definition of the molecular and cellular mechanisms in DCs that balance the pro- and anti-inflammatory immune response to self after cell death; and (2) translational exploitation of these mechanistic insights in order to devise effective therapeutic and preventive cancer vaccines. PUBLIC HEALTH RELEVANCE: Vaccination with apoptotic autologous tumor cells represents a particularly promising way to target the greatest number of potential antigens without the need for their individual identification. However, Cross- presentation of cell-associated antigens from apoptotic cells by DC generally leads to the induction of T cell tolerance. We have identified a new DC subset that is capable to prime T cells to cell associated antigen. In this project we will define the molecular and cellular mechanisms in these DCs that confer the T cell priming capacity in order to translational exploit of these mechanistic insights for the design of effective therapeutic and preventive cancer vaccines. .