Tumor Vaccination: Modulation of Inhibitory Signaling in Antigen-presenting cells

描述(由申请人提供)：需要一种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反应。树突状细胞(DC)在启动和维持免疫应答中起关键作用，受刺激信号和抑制信号的调节。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DC中细胞因子信号转导抑制因子1(SOCS1)的关键控制，SOCS1沉默的DC具有高度激活和增强的免疫刺激能力，能够诱导抗原特异性的CTL反应。本研究的目的是开发一种新的免疫策略，通过抑制DC中的细胞因子信号抑制来克服肿瘤介导的免疫抑制。本研究的中心假设是，沉默SOCS1可以使不受约束的促炎STATS信号对抗DC中的抗炎STATS信号，导致克服肿瘤介导的免疫抑制，并诱导有效的抗肿瘤反应。本研究的具体目的是：目标1)。为了验证一种假设，即在DC中沉默SOCS1将允许不受限制的促炎STATS信号来对抗肿瘤衍生因子介导的抗炎STAT3信号，从而克服肿瘤介导的免疫抑制并诱导有效的抗肿瘤反应。目标2)。为了验证荷瘤小鼠中SOCS1沉默、高激活的DC持续激活的自身反应性CTL是否对肿瘤免疫抑制具有抵抗力的假设。目标3)。为了验证肿瘤环境中SOCS1沉默、高激活的DC可以诱导针对自身Trp2的长期CTL反应的假设。这项研究的意义有两个方面：第一，这项研究将导致新型肿瘤疫苗的开发，这些疫苗能够通过禁用DC上的信号抑制因子，如SOCS1，来克服肿瘤介导的免疫抑制和打破自身耐受；第二，本研究有助于阐明肿瘤环境中DC调节T细胞激活和抗原提呈的机制。

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.