TGF-β mediated epigenetic control of anti-tumor natural killer cells in primary liver cancer

TGF-β 介导的原发性肝癌抗肿瘤自然杀伤细胞的表观遗传控制

• 批准号: 460245557
• 负责人: Dr. Gabriela Wiedemann
• 金额: --
• 依托单位: Klinik und Poliklinik für Innere Medizin II: Gastroenterologie
• 依托单位国家: 德国
• 项目类别: Independent Junior Research Groups
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/460245557?language=en
• 关键词: TGF; mediated; epigenetic; control; anti

Natural killer (NK) cells are cytotoxic innate lymphoid cells defined by the capacity to rapidly target infected and malignant cells without prior sensitization. Thus, they have long been appreciated as a central player in the anti-tumoral immune response. However, cancers have found intricate ways of evading NK cell-mediated killing, and NK cells in advanced solid cancers are often scarce and functionally impaired. A central pathway of tumor induced immunosuppression is TGF-β signaling. Increased levels of TGF-β have been described in many solid tumors and the immunosuppressive effects of TGF-β signaling are versatile: apart from shaping the adaptive immune response, TGF-β has also been shown to impede NK cell functions, e.g. by down-regulation of activating receptors and inhibition of interferon (IFN)-γ production. However, the exact mechanisms by which TGF-β regulates NK cell responses have not been investigated. The aim of this project is to identify TGF-β target genes in NK cells and to delineate their role in tumor-associated NK cells. In her previous research projects, the applicant has gained expertise in the analysis of tumor-immune cell interactions and in the analysis of transcriptional and epigenetic cytokine networks in NK cells. The host institute can provide the technical equipment for the molecular analyses, state-of-the-art genetically engineered murine tumor models and tissue samples from cancer patients. First, we will conduct a genome-wide analysis of TGF-β transcriptional target genes and TGF-β induced epigenetic modifications in NK cells. Secondly, top target genes of TGF-β signaling in NK cells will be analyzed in murine models of cholangiocellular carcinoma (CCA) and hepatocellular carcinomas (HCC) over the course of tumor formation and progression. Finally, human CCA and HCC tissues will be analyzed for NK cell infiltration and expression of TGF-β target genes and their impact on the patients’ prognosis. The results of this project will provide invaluable new insights into how NK cell functions are shaped by the tumor microenvironment (TME) and will help to further develop NK cell-based immunotherapeutic approaches in cancer therapy.

自然杀伤 (NK) 细胞是具有细胞毒性的先天淋巴细胞，具有快速靶向感染细胞和恶性细胞且无需事先致敏的能力。因此，它们长期以来一直被认为是抗肿瘤免疫反应的核心参与者。然而，癌症已经找到了逃避 NK 细胞介导的杀伤的复杂方法，并且晚期实体癌中的 NK 细胞通常稀缺且功能受损。肿瘤诱导的免疫抑制的一个中心途径是 TGF-β 信号传导。在许多实体瘤中，TGF-β 水平升高，并且 TGF-β 信号传导的免疫抑制作用是多方面的：除了塑造适应性免疫反应外，TGF-β 还被证明会阻碍 NK 细胞功能，例如，NK 细胞。通过下调激活受体和抑制干扰素 (IFN)-γ 的产生。然而，TGF-β 调节 NK 细胞反应的确切机制尚未得到研究。该项目的目的是鉴定 NK 细胞中的 TGF-β 靶基因并描述它们在肿瘤相关 NK 细胞中的作用。在她之前的研究项目中，申请人获得了分析肿瘤-免疫细胞相互作用以及分析 NK 细胞转录和表观遗传细胞因子网络的专业知识。主办机构可以提供分子分析、最先进的基因工程小鼠肿瘤模型和癌症患者组织样本的技术设备。首先，我们将对 NK 细胞中 TGF-β 转录靶基因和 TGF-β 诱导的表观遗传修饰进行全基因组分析。其次，将在胆管细胞癌（CCA）和肝细胞癌（HCC）的小鼠模型中分析肿瘤形成和进展过程中 NK 细胞中 TGF-β 信号传导的主要靶基因。最后，将分析人类 CCA 和 HCC 组织的 NK 细胞浸润和 TGF-β 靶基因的表达及其对患者预后的影响。该项目的结果将为了解 NK 细胞功能如何受肿瘤微环境 (TME) 影响提供宝贵的新见解，并将有助于进一步开发基于 NK 细胞的癌症治疗免疫治疗方法。