Plasmacytoid DC Interactions in the Generation of an Antitumor Immune Response

描述(申请人提供)：尽管对病毒感染的免疫反应通常是有效的，但与之形成对比的是，自然产生的抗肿瘤免疫反应往往很弱。将抗病毒免疫反应的成分应用于肿瘤免疫学是产生更有效的抗肿瘤反应的一种潜在的有前途的策略。细胞毒性T细胞(CTL)介导的强适应性免疫反应依赖于天然免疫系统的初始激活。浆细胞样树突状细胞(PDC)是天然免疫细胞的一个亚群，能在病毒刺激下产生高水平的I型干扰素，在调节针对病毒感染的先天性和获得性免疫中发挥核心作用。在这个方案中，我们将系统地评估pDC通过与传统的髓系树突状细胞(MDCs)和自然杀伤(NK)细胞的相互作用来诱导增强的CTL介导的抗肿瘤反应的机制。在我们的初步研究中，我们发现激活的、抗原致敏的、PDC和MDC分别能刺激小鼠的抗原特异性CTL反应。然而，用活化的pDC和MDCs的混合物免疫可以显著增强抗原特异性CTL的诱导，从而改善抗肿瘤反应，我们推测这是由于pDC增强了mDC的激活。此外，我们还发现活化的pDC能够在体外和体内激活NK细胞，并可能刺激NK细胞的趋化作用。重要的是，瘤内注射活化的pDC导致了体内以NK细胞依赖的方式交叉启动肿瘤抗原特异性CTL。我们推测，PDC介导的NK细胞激活导致肿瘤细胞裂解增加，随后局部激活的MDCs摄取和交叉递呈肿瘤抗原，从而导致肿瘤抗原特异性CTL的启动。在以下特定目标中，我们建议定义这些细胞相互作用的机制，以便最终将这些概念应用于在患者中产生更成功的抗肿瘤免疫反应：(1)描述PDC和MDC之间的相互作用，它们在诱导抗原特异性T细胞方面的协同作用；(2)确定PDDC和NK细胞可以增强针对肿瘤衍生抗原的T细胞交叉激发的机制。(3)明确pDC诱导MDC成熟和NK细胞活化积聚的分子机制。

DESCRIPTION (provided by applicant): Although the immune response against viral infections is generally potent, naturally generated antitumor immune responses are often weak by contrast. Applying the components of antiviral immune responses to tumor immunology is a potentially promising strategy towards the generation of a more effective antitumor response. Strong adaptive, cytotoxic T cell (CTL)-mediated immune responses are known to be dependent on initial activation of the innate immune system. Plasmacytoid dendritic cells (pDCs), a subset of innate immune cells that produce high levels of type I interferons on viral stimulation, play a central role in modulating innate and adaptive immunity against viral infections. In this proposal, we will systematically evaluate the mechanisms by which pDCs can induce augmented CTL-mediated antitumor responses through their interactions with conventional myeloid dendritic cells (mDCs) and natural killer (NK) cells. In our preliminary studies, we found that activated, antigen-pulsed, pDC and mDC could individually stimulate antigen-specific CTL responses in mice. However, immunization with a mixture of activated pDCs and mDCs led to a markedly enhanced induction of antigen-specific CTLs resulting in an improved antitumor response, which we hypothesize is due to augmentation of mDC activation by pDCs. In addition, we found that activated pDCs are capable of activating NK cells in vitro and in vivo and may also stimulate NK cell chemotaxis. Importantly, intratumoral injection of activated pDCs resulted in the in vivo cross-priming of tumor antigen-specific CTLs in an NK cell-dependent manner. We hypothesize that pDC-mediated activation of NK cells resulted in increased tumor cell lysis and subsequent uptake and cross-presentation of tumor antigen by locally activated mDCs, leading to tumor antigen-specific CTL priming. In the following Specific Aims, we propose to define the mechanisms of these cellular interactions in order to ultimately apply these concepts to the generation of a more successful antitumor immune response in patients: (1) Characterize the interactions between pDC and mDC that underly their synergy in the induction of antigen-specific T-cells (2) Determine the mechanisms by which pDCs and NK cells can augment T-cell cross-priming against tumor-derived antigens. (3) Define the molecular mechanisms through which pDCs induce mDC maturation and NK cell activation and accumulation.