Tumor vaccination by modulation of inhibitory signaling in antigen-presenting cel

描述（由申请方提供）：需要有效的肿瘤疫苗来诱导能够克服肿瘤介导的免疫抑制的抗原特异性应答。树突状细胞（Dendritic cells，DC）在免疫应答的启动和维持中起关键作用，受刺激性和抑制性信号的调节。我们最近的研究表明，DC的抗原提呈能力和获得性免疫的大小受到DC中细胞因子信号转导抑制因子1（SOCS 1）的关键控制，并且SOCS 1沉默的DC被过度激活，并且具有增强的免疫刺激能力以诱导抗原特异性CTL应答。本研究的目的是开发一种新的免疫策略，以克服肿瘤介导的免疫抑制，通过抑制细胞因子信号抑制剂在树突状细胞。本研究的中心假设是，沉默SOCS 1允许不受约束的促炎性STATs信号传导拮抗DC中的抗炎性STATs信号传导，从而克服肿瘤介导的免疫抑制并诱导有效的抗肿瘤应答。本研究的具体目标是：目标1）。为了验证这一假设，即DC中的SOCS 1沉默将允许不受约束的促炎性STATs信号传导拮抗肿瘤衍生因子介导的抗炎性STAT 3信号传导，从而克服肿瘤介导的免疫抑制并诱导有效的抗肿瘤应答。目标2）。为了检验荷瘤小鼠中被SOCS 1沉默的、过度活化的DC持续活化的自身反应性CTL对肿瘤免疫抑制具有抗性的假设。目标3）。为了验证肿瘤环境中SOCS 1沉默、过度活化的DC可以诱导针对自身TRP 2的长期CTL应答的假设。这项研究的意义是双重的：首先，这项研究将导致开发新的肿瘤疫苗，能够克服肿瘤介导的免疫抑制和破坏自身耐受，通过禁用信号传导抑制剂，如SOCS 1在DC;第二，这项研究有助于阐明调节T细胞活化和抗原呈递的机制，在肿瘤环境中的DC。

DESCRIPTION (provided by applicant): An effective tumor vaccine is required to induce antigen-specific responses that are able to overcome tumor-mediated immune suppression. Dendritic cells (DCs) play a critical role in the initiation and maintenance of immune response and are regulated by stimulatory as well as inhibitory signaling. Our recent studies demonstrate that the antigen presentation capacity of DCs and the magnitude of adaptive immunity are critically controlled by the suppressor of cytokine signaling 1 (SOCS1) in DCs, and SOCS1-silenced DCs are hyperactivated and have an enhanced immunostimulatory capacity to induce antigen- specific CTL responses. The goal of this study is to develop a novel immunization strategy to overcome tumor-mediated immunosuppression by inhibiting a cytokine signaling inhibitor in DCs. The central hypothesis of this study is that silencing SOCS1 allows unbridled pro-inflammatory STATs signaling to antagonize anti-inflammatory STATS signaling in DCs, leading to the overcoming of tumor-mediated immune suppression and induction of effective antitumor responses. The specific aims of this study are: Aim 1). To test the hypothesis that SOCS1 silencing in DCs will allow unbridled pro-inflammatory STATs signaling to antagonize tumor-derived factors-mediated anti-inflammatory STAT3 signaling, leading to the overcoming of tumor-mediated immune suppression and induction of effective antitumor responses. Aim 2). To test the hypothesis that self-reactive CTLs that are persistently activated by SOCS1-silenced, hyperactivated DCs in tumor-bearing mice are resistant to tumor immunosuppression. Aim 3). To test the hypothesis that SOCS1-silenced, hyperactivated DCs in the tumor environment can induce a long- term CTL response against self TRP2. The significance of this study is twofold: first, this study will lead to the development of novel tumor vaccines capable of overcoming tumor-mediated immunosuppression and breaking self tolerance by disabling signaling inhibitors such as SOCS1 in DCs; and second, this study contributes to elucidating the mechanisms that regulate T-cell activation and antigen-presentation by DCs in the tumor environment.