Inhibitory receptor repertoire of anti-tumoral NK cells in mouse MHC-I-deficient cancers

小鼠 MHC-I 缺陷型癌症中抗肿瘤 NK 细胞的抑制性受体库

• 批准号: 389276769
• 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: Research Fellowships
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/389276769?language=en
• 关键词: Inhibitory; receptor; repertoire; anti; tumoral

Natural killer cells (NK cells) are lymphoid cells of the innate immune system. They have been identified by their capacity to rapidly kill tumor cells or virus-infected cells without prior sensitization. For target cell recognition, NK cells are endowed with an abundant repertoire of activating and inhibiting receptors, which allows them to recognize stress ligands and MHC class I (MHC-I) downregulation on infected cells and cancer cells. Upon recognition, NK cells are able to rapidly kill their targets. In the past decade, T cell-targeted immunological cancer therapies have shown great success and many have quickly entered FDA approval. However, a significant number of cancers downregulate MHC-I on their surface to escape T cell mediated killing. As NK cells effectively recognize and eliminate these MHC-I low tumor cells, these tumor types are specifically prone to NK cell therapies. This project aims at investigating NK cell subsets with a high potential of killing MHC-I low tumors and increasing their therapeutic potential. By analyzing the dynamic phenotypic changes of NK cells in MHC-I low tumors, a tumor-reactive NK cell subset was defined. Now, strategies to expand this subset and to increase its cytotoxicity will be examined. This project is an important step towards the development of clinical cancer therapies exploiting the cytotoxic capacities of NK cells.

自然杀伤细胞(NK细胞)是先天免疫系统的淋巴样细胞。它们的鉴定是因为它们能够在不事先致敏的情况下快速杀死肿瘤细胞或病毒感染的细胞。在靶细胞识别方面，NK细胞被赋予了丰富的激活和抑制受体的能力，这使得它们能够识别应激配体和感染细胞和癌细胞上MHC-I类(MHC-I)的下调。一旦被识别，NK细胞就能够迅速杀死他们的目标。在过去的十年中，T细胞靶向免疫癌症疗法取得了巨大的成功，许多疗法很快就进入了FDA的批准。然而，相当数量的癌症在其表面下调MHC-I以逃避T细胞介导的杀伤。由于NK细胞有效地识别和消除这些MHC-I低肿瘤细胞，这些肿瘤类型特别容易进行NK细胞治疗。本项目旨在研究具有高杀伤MHC-I低度肿瘤潜能的NK细胞亚群，以提高其治疗潜能。通过分析MHC-I低度肿瘤患者NK细胞表型的动态变化，定义了肿瘤反应性NK细胞亚群。现在，将研究扩大这一亚群并增加其细胞毒性的策略。这个项目是开发利用NK细胞的细胞毒能力的临床癌症治疗的重要一步。