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

肝细胞癌（HCC）是全球第六大常见癌症，发病率呈上升趋势。由于治疗选择有限，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改善患者护理具有很高的临床意义。旨在诱导或促进肿瘤特异性CD8+ T细胞反应的免疫疗法是HCC患者的一种有希望的创新治疗选择。然而，几种抑制机制导致自然发生的抗肿瘤免疫反应失败。为了开发有效的免疫治疗策略，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但密切相关的HCC免疫学课题。在第一部分中，自然杀伤细胞（NK细胞）的抑制潜力将被解决。在慢性乙型肝炎感染中，NK细胞是抗病毒CD8+ T细胞的重要抑制剂。重要的是，T细胞衰竭的机制在HCC和慢性乙型肝炎感染之间重叠，因此，NK细胞在HCC患者中很可能具有类似的抑制潜能。在拟建的研究项目中，将分析由NK细胞缺失或抑制引起的抗肿瘤T细胞失败。计划项目的第二部分将重点研究抑制性受体程序性死亡(PD)-1。阻断PD-1或其配体（PD-L1）的靶向治疗在首次临床试验中显示出令人鼓舞的结果。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患者中研究，但抗肿瘤免疫反应的诱导是可以预期的。因此，将首次分析这种免疫治疗方法对抗肿瘤CD8+ T细胞的影响。这具有很高的临床相关性，因为有相当数量的患者对这种治疗没有反应。因此，特别是在没有临床获益的患者中，我们期望额外的抑制机制，例如NK细胞/T细胞相互作用，将在这个特殊的患者队列中进一步分析。更好地了解阻断PD-1/PD-L1信号通路的免疫学机制以及分析NK细胞的抑制潜力将有助于优化免疫治疗。这对改善晚期肿瘤患者的护理具有重要的临床意义。

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.