In vivo RNAi screen to identify new inhibitory targets in tumour-specific T lymphocytes during liver cancer development

体内 RNAi 筛选以鉴定肝癌发展过程中肿瘤特异性 T 淋巴细胞的新抑制靶点

• 批准号: 270823663
• 负责人: Dr. Tetyana Yevsa, Ph.D.
• 金额: --
• 依托单位: Helmholtz-Zentrum für Infektionsforschung (HZI)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/270823663?language=en
• 关键词: vivo; RNAi; screen; identify; new

We have recently found that induction of Th1-polarized adaptive immunity was crucial for suppression of NrasG12V-expressing liver tumours (Kang & Yevsa et al, Nature, 2011). Our data and data obtained from patients with liver- and other malignancies imply a central role of T cells in modulating tumour progression. However, liver tumor microenvironment continuously inhibits T cell immune responses. We hypothesize, that the majority of inhibitory factors (genes) in T cells remains unknown and to identify the main T cell inhibitory genes, we propose to perform an in vivo RNAi screen using a thematically focused shRNA library targeting a list of genes up-regulated in memory T cells during liver cancer development. We will use a combination of mir30-based RNAi- and transposon mediated oncogene delivery platforms, recently established in our studies (Kang & Yevsa, et al, Nature, 2011; Wüstefeld et al, Cell, 2013). Importantly, in the liver cancer model that we are going to use, liver tumours develop similarly to human tumours and are not based on cell transplantation. To our knowledge until now nobody has performed a similar RNAi screen in immune system in mice bearing liver malignancies. The proposed project has a great promise for later preclinical and clinical strategies for T cell-immunotherapy in cancer patients. Blocking of inhibitory molecules in T cells either alone or in combination with additional (immuno-) therapy will significantly inhibit tumour growth and increase the overall survival of patients with hepatic malignancies.

我们最近发现，诱导Thl极化的适应性免疫对于抑制表达NrasG 12 V的肝肿瘤是至关重要的（Kang & Yevsa等人，Nature，2011）。我们的数据以及从肝脏和其他恶性肿瘤患者中获得的数据表明T细胞在调节肿瘤进展中发挥着核心作用。然而，肝肿瘤微环境持续抑制T细胞免疫应答。我们假设，T细胞中的大多数抑制因子（基因）仍然未知，为了鉴定主要的T细胞抑制基因，我们建议使用主题聚焦的shRNA文库进行体内RNAi筛选，靶向肝癌发展过程中记忆T细胞中上调的一系列基因。我们将使用最近在我们的研究中建立的基于mir 30的RNAi和转座子介导的癌基因递送平台的组合（Kang & Yevsa等人，Nature，2011; Wüstefeld等人，Cell，2013）。重要的是，在我们将要使用的肝癌模型中，肝脏肿瘤的发展与人类肿瘤相似，并且不是基于细胞移植。据我们所知，到目前为止，还没有人在携带肝脏恶性肿瘤的小鼠的免疫系统中进行类似的RNAi筛选。所提出的项目对于癌症患者T细胞免疫治疗的后期临床前和临床策略具有很大的希望。阻断T细胞中的抑制分子，无论是单独或与其他（免疫）治疗相结合，将显着抑制肿瘤生长，并增加肝脏恶性肿瘤患者的总生存期。