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抗原特异性反应，能够克服肿瘤介导的免疫抑制。树突状细胞（dc）在免疫应答的启动和维持中起着关键作用，并受到刺激和抑制信号的调节。我们最近的研究表明，dc的抗原呈递能力和适应性免疫的大小受到dc中细胞因子信号1抑制因子（SOCS1）的关键控制，SOCS1沉默的dc过度激活，并具有增强的免疫刺激能力，以诱导抗原特异性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剂来克服肿瘤介导的免疫抑制。本研究的中心假设是，沉默SOCS1允许无节制的促炎STATs信号对抗dc中的抗炎STATs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。本研究的具体目的是：目的1)。为了验证以下假设：dc中SOCS1的沉默将允许无节制的促炎stat信号拮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。2)目标。为了验证荷瘤小鼠中被socs1沉默、高激活的dc持续激活的自反应性ctl对肿瘤免疫抑制具有抗性的假设。目标3)。为了验证socs1沉默、肿瘤环境中过度激活的dc可以诱导针对自身TRP2的长期CTL反应的假设。该研究具有双重意义：首先，该研究将导致新型肿瘤疫苗的开发，这些疫苗能够克服肿瘤介导的免疫抑制，并通过使DCs中的信号抑制剂（如SOCS1）失能来打破自身耐受性；第二，本研究有助于阐明dc在肿瘤环境中调节t细胞活化和抗原呈递的机制。

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.