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

描述（由申请方提供）：治疗性癌症疫苗旨在驱动免疫系统的特异性激活，用于治疗现有恶性肿瘤或预防其复发。这需要强大的疫苗接种策略，因为肿瘤预先存在免疫抑制机制。从理论上讲，用凋亡的自体肿瘤细胞进行疫苗接种代表了一种特别有前途的方法，可以靶向最大数量的潜在抗原，而不需要对其进行单独鉴定。然而，凋亡细胞的感知和清除通常被认为是非炎症或甚至耐受性过程。流行的观点是，由正常组织更新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，在局部淋巴结中它们诱导T细胞耐受、T细胞无反应性或T细胞缺失，以维持组织稳态并防止宿主中的自身免疫。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亚群相比，它在摄取凋亡物质后，有效地（交叉）引发CD 4+和CD 8 +T细胞与细胞相关抗原。nDC的有效佐剂活性在很大程度上取决于它们在与凋亡细胞相互作用后产生I型IFN。由nDC引发的T细胞在每个细胞的基础上显示出比由其他DC亚群引发的T细胞更大的初级扩增、细胞因子产生和记忆形成的能力。因此，当暴露于凋亡肿瘤细胞时，这些nDC在疫苗接种和治疗环境中诱导保护性抗肿瘤应答方面都是极其有效的。我们提出的研究的核心假设是，暴露于凋亡细胞的nDC的I型IFN生产是至关重要的nDC功能和随后的启动保护性T细胞对细胞相关抗原的反应。这项工作的长期目标是双重的：（1）在细胞死亡后平衡对自身的促炎和抗炎免疫应答的DC中的分子和细胞机制的定义;和（2）这些机制见解的转化利用，以设计有效的治疗和预防癌症疫苗。 公共卫生相关性：用凋亡的自体肿瘤细胞进行疫苗接种代表了一种特别有前途的方法，可以靶向最大数量的潜在抗原，而不需要对其进行单独鉴定。然而，DC对来自凋亡细胞的细胞相关抗原的交叉呈递通常导致T细胞耐受的诱导。我们已经鉴定了一种新的DC亚群，其能够将T细胞引发至细胞相关抗原。在这个项目中，我们将定义这些DC中赋予T细胞引发能力的分子和细胞机制，以便将这些机制的见解转化为有效的治疗和预防癌症疫苗的设计。.

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. .