Plasmacytoid DC Interactions in the Generation of an Antitumor Immune Response

描述（由申请人提供）：尽管针对病毒感染的免疫应答通常是有效的，但相比之下，天然产生的抗肿瘤免疫应答通常较弱。将抗病毒免疫应答的组分应用于肿瘤免疫学是产生更有效的抗肿瘤应答的潜在有前途的策略。已知强适应性细胞毒性T细胞（CTL）介导的免疫应答依赖于先天免疫系统的初始激活。浆细胞样树突状细胞（pDC）是在病毒刺激下产生高水平I型干扰素的先天免疫细胞的子集，在调节针对病毒感染的先天免疫和适应性免疫中发挥核心作用。在这个提议中，我们将系统地评估pDCs通过与传统的髓样树突状细胞（mDCs）和自然杀伤（NK）细胞的相互作用诱导增强CTL介导的抗肿瘤反应的机制。在我们的初步研究中，我们发现活化的抗原脉冲的pDC和mDC可以单独地刺激小鼠的抗原特异性CTL应答。然而，用活化的pDC和mDC的混合物免疫导致抗原特异性CTL的诱导显著增强，从而导致抗肿瘤应答的改善，我们假设这是由于pDC增强mDC活化。此外，我们发现活化的pDC能够在体外和体内活化NK细胞，并且还可以刺激NK细胞的趋化性。重要的是，肿瘤内注射活化的pDC导致肿瘤抗原特异性CTL以NK细胞依赖性方式的体内交叉引发。我们假设pDC介导的NK细胞活化导致肿瘤细胞溶解增加，随后通过局部活化的mDC摄取和交叉呈递肿瘤抗原，导致肿瘤抗原特异性CTL引发。在以下具体目标中，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应答：（1）表征pDC和mDC之间的相互作用，所述相互作用是它们在诱导抗原特异性T细胞中协同作用的基础。针对肿瘤来源的抗原引发。(3)定义pDC诱导mDC成熟和NK细胞活化和积累的分子机制。

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.