Induction of cytotoxic T cells by pulmonary dendritic cells

描述(申请人提供)：癌症是现代最持久的健康问题之一。利用免疫学技术的最新发展为开发针对免疫原性癌症的疫苗提供了实质性的新希望。在过去的一年里，我们一直在开发一种方法来训练内源性免疫系统识别和靶向肿瘤细胞。这种方法利用树突状细胞(DC)识别抗原的特殊功能，并诱导NA？VE T细胞分化为细胞毒性T细胞，以消除肿瘤细胞。虽然这种方法前景看好，但我们相信，通过利用存在于组织中的特定DC亚型所扮演的不同功能角色，基于DC的癌症疫苗的开发将得到实质性的加强。这项提案将重点放在肺上，并概述了旨在采取几个关键步骤来更完整地描述这一系统并将其开发为癌症可行治疗方法的实验。我们的初步实验表明，两种肺树突状细胞都有独特的特征。我们和其他人已经证明，肺树突状细胞不同地表达模式识别受体(如TLR)，获得抗原，并呈递抗原。我们的中心假设是TLR3+CD103+DC和TLR7+CD11bi肺树突状细胞都具有促进针对肿瘤相关抗原的细胞毒T细胞的发展的能力。然而，只有当DC同时1)呈递抗原和2)适当地被其相应的TLR激动剂刺激时，这才是正确的。该提案涉及一些需要解决的关键问题，以便充分说明该系统的特点，并开始将这一方法转化为人类。在目标1中，我们将展示肺DC亚型在TLR3或TLR7配体存在的情况下促进细胞毒作用的独特能力。这将填补我们在体内DC功能和TLR表达和激活的选择性机制方面的关键知识空白。在目标2中，我们将研究激活的DC亚群产生的细胞因子(S)促进细胞毒性T细胞的分化。这一目标将有助于确定内源性DC选择性地用于分化T细胞的机制。最后，在目标3中，我们将在转移性肺癌模型中测试基于TLR3+CD103+DC和TLR7+CD11bhi DC的治疗的抗肿瘤特性。初步数据表明，即使是侵袭性的癌症，特定的DC靶向方法也可以显著缩小肿瘤大小。然而，要充分描述和发展这一模式，还需要做更多的工作。总体而言，实现这些目标将在理解肺树突状细胞的功能作用方面取得实质性进展，并探索它们在开发内源性抗癌疫苗方面的潜在用途。

DESCRIPTION (provided by applicant): Cancer is one of the most enduring health problems of the modern era. Recent developments using immunological techniques offer substantial new promise for developing vaccines against immunogenic cancers. Over the past year, we have been developing a method for educating the endogenous immune system to recognize and target tumor cells. The approach capitalizes on the specialized functions of dendritic cells (DCs) to recognize antigens and induce differentiation of na¿ve T cells into cytotoxic T cells to eliminate tumor cells. While this approach is highly promising, we believe that the development of DC-based cancer vaccines will be substantially enhanced by exploiting the different functional roles played by specific DC subtypes present in tissues. This proposal focuses on the lung, and outlines experiments designed to take several critical steps towards characterizing this system more completely and developing it as a viable treatment for cancer. Our preliminary experiments have shown that there are unique features in both pulmonary DCs. We and others have demonstrated that pulmonary DCs differentially express pattern recognition receptors (such as TLRs), acquire antigen, and present antigen. Our central hypothesis is that both TLR3+CD103+ DC and TLR7+CD11bhi lung DCs, possess the capacity to promote the development of cytotoxic T cells directed to tumor-associated antigens. However, this is only true if the DC is simultaneously 1) presenting the antigen and 2) appropriately stimulated by its corresponding TLR agonist. The proposal addresses a number of critical questions that require resolution in order to fully characterize the system and begin to translate this approach to humans. In Aim 1, we will demonstrate the unique ability of pulmonary DC subtypes to promote cytotoxicity in the presence of either TLR3 or TLR7 ligands. This will fill critical gaps in our knowledge of the mechanisms underlying in vivo DC function and selectivity of TLR expression and activation. In Aim 2, we will investigate the cytokine(s) produced by the activated DC subtype promoting differentiation of cytotoxic T cells. This aim will help define the mechanisms selectively used by endogenous DCs to differentiate T cells. Finally in Aim 3, we will test the anti-tumor properties of pulmonary TLR3+CD103+ DC and TLR7+CD11bhi DC-based treatments in a metastatic lung cancer model. Preliminary data suggest that the specific DC targeting approach may dramatically reduce tumor size in even an aggressive form of cancer. However, more work is needed to fully characterize and develop this model. Overall, achieving these aims will provide substantial advances in understanding the functional roles of lung dendritic cells and explore their potential use in developing endogenous anti-cancer vaccines.