Beyond checkpoint inhibitors: Natural killer cells limiting antitumor T cell immunity in hepatocellular carcinoma

超越检查点抑制剂：自然杀伤细胞限制肝细胞癌中的抗肿瘤 T 细胞免疫

• 批准号: 323178777
• 负责人: Dr. Nathalie Schmidt
• 金额: --
• 依托单位: Klinik für Innere Medizin II - Gastroenterologie, Hepatologie, Endokrinologie und Infektiologie
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2017-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/323178777?language=en
• 关键词: Beyond; checkpoint; inhibitors; Natural; killer

Hepatocellular Carcinoma (HCC) is the sixth most common cancer worldwide with a rising incidence. Due to limited therapeutic options, HCC is the second leading cause of cancer related death. Thus, the development of new therapeutic approaches is of a high clinical relevance to improve patient care. Immunotherapies with the aim to induce or boost tumor-specific CD8+ T cell responses constitute a promising, innovative treatment option for patients with HCC. However, several inhibitory mechanisms contribute to a failure of naturally occurring antitumoral immune responses. In order to develop efficient immunotherapeutic strategies, a thorough understanding of these inhibitory mechanisms is of high importance. To address these inhibitory mechanisms, my work program will be dived into two independent, but closely related topics of HCC immunology. In the first part, the inhibitory potential of natural killer cells (NK cells) will be addressed. In chronic hepatitis B infection, NK cells are an important inhibitor of antiviral CD8+ T cells. Importantly, the mechanisms of T cell failure overlap between HCC and chronic hepatitis B infection, thus, a similar inhibitory potential of NK cells in patients with HCC is very likely. In the proposed research project, a failure of antitumoral T cells caused by a deletion or inhibition by NK cells will be analyzed.The second part of the planned project will focus on the inhibitory receptor programmed death (PD)-1. Targeted therapies blocking PD-1 or its ligand (PD-L1) have shown promising results in first clinical trials. However, the exact immunological mechanism leading to this observed clinical response has not been investigated in patients with HCC, but an induction of antitumoral immune responses is expectable. Thus, for the first time the effect of this immunotherapeutic approach on antitumoral CD8+ T cells will be analyzed. This is of high clinical relevance, because a relevant number of patients fails to respond to this treatment. Thus, especially in patients without clinical benefit of this therapy, we expect additional inhibitory mechanisms, e.g. NK cell/T cell interactions, that will be further analyzed in this special patient cohort.A better understanding of the immunological mechanisms of blocking the PD-1/PD-L1 signaling pathway as well as the analysis of the inhibitory potential of NK cells will facilitate an optimization of immunotherapy. This is of high clinical relevance to improve the care of patients with advanced tumors.

肝细胞癌（HCC）是世界上第六大常见癌症，发病率不断上升。由于有限的治疗选择，HCC是癌症相关死亡的第二大原因。因此，开发新的治疗方法对于改善患者护理具有高度的临床相关性。旨在诱导或增强肿瘤特异性CD 8 + T细胞应答的免疫疗法为HCC患者提供了一种有前景的创新治疗选择。然而，几种抑制机制导致自然发生的抗肿瘤免疫应答失败。为了开发有效的免疫抑制策略，深入了解这些抑制机制是非常重要的。为了解决这些抑制机制，我的工作计划将分为两个独立的，但密切相关的HCC免疫学主题。在第一部分中，自然杀伤细胞（NK细胞）的抑制潜力将得到解决。在慢性B型肝炎感染中，NK细胞是抗病毒CD 8 + T细胞的重要抑制剂。重要的是，T细胞衰竭的机制在HCC和慢性B型肝炎感染之间重叠，因此，HCC患者中NK细胞的类似抑制潜力是非常可能的。本研究计划的第二部分将对NK细胞的缺失或抑制导致的抗肿瘤T细胞的失败进行分析。本研究计划的第二部分将重点关注抑制性受体程序性死亡（PD）-1。阻断PD-1或其配体（PD-L1）的靶向治疗在第一次临床试验中显示出有希望的结果。然而，导致这种观察到的临床反应的确切免疫学机制尚未在HCC患者中进行研究，但诱导抗肿瘤免疫反应是可以预期的。因此，将首次分析这种免疫方法对抗肿瘤CD 8 + T细胞的影响。这具有高度的临床相关性，因为相关数量的患者对这种治疗没有反应。因此，对于PD-1/PD-L1信号通路阻断的免疫学机制以及NK细胞的抑制潜力的分析，将有助于优化免疫治疗方案。这对于改善晚期肿瘤患者的护理具有高度的临床相关性。