HCC immunology: correlating immune profiles to specific response to immunotherapy

肝癌是世界范围内死亡率和发病率都在上升的少数恶性肿瘤之一，也是癌症相关死亡的第二大原因。尽管如此，几乎一半的HCC患者直到疾病的晚期才被诊断出来，诸如切除和移植的治愈性治疗仅可用于有限数量的患者。目前，唯一可用的全身治疗是多酪氨酸激酶抑制剂索拉非尼以及乐伐替尼和瑞格非尼，其生存获益有限。因此，有必要改善这些患者的治疗选择。本项目包括三条调查线：首先，本项目旨在破译决定HCC癌症免疫的分子元件。这是基于这样一个事实，即尽管在动物模型中取得了有希望的结果，但几项临床试验未能使用各种检查点抑制剂获得生存益处。对这些试验的批评主要集中在一般的治疗方法上。因此，了解癌细胞和微环境之间的相互作用，决定最近描述的免疫谱的肿瘤免疫原性的机制以及它们如何与对治疗的特异性反应相关是至关重要的。第二，通过彻底表征肿瘤组织和配对的外周血免疫细胞和细胞因子的组成，通过该项目，可以提供非侵入性工具来识别属于不同HCC免疫谱的患者。此外，突变的循环肿瘤DNA将被评估作为一种工具，以跟踪候选驱动程序的反应或耐药性的免疫疗法。第三，基因工程小鼠模型能够模拟肝癌免疫概况将在这个项目中产生。随后，具有不同特征的小鼠将暴露于各种免疫疗法，以进一步探索治疗策略并提高目前可用的免疫疗法的功效。

Liver cancer is one of the few malignancies with both rising mortality and incidence and the second leading cause of cancer related mortality worldwide. As still, almost half of the patients with HCC are not diagnosed until advanced stages of the disease, curative treatments such as resection and transplantation are only available for a limited amount of patients. Currently, the only systemic therapy available is the multi-tyrosine kinase inhibitor sorafenib alongside lenvatinib and regorafenib with limited survival benefit.Accordingly there is a substantial need for improving the therapeutic options for these patients.This project includes three lines of inquiry:First, this project aims at deciphering molecular elements that determine cancer immunity in HCC. This is based on the fact that, despite promising results in animal models, several clinical trials have failed to elicit a survival benefit using various checkpoint-inhibitors. Criticism of these trials has largely focused on the generalised treatment approaches.Therefore, understanding the interplay between cancer cells and the microenvironment, mechanisms determining tumor immunogenicity of the recently described immune profiles and how they correlate to specific responses to therapy is of critical importance.Second, by thoroughly characterizing the composition of tumor tissue and paired peripheral blood immune cells and cytokines, non-invasive tools could, through this project, be provided for the identification of patients belonging to the distinct HCC immune profiles. In addition, mutant circulating tumor DNA will be assessed as a tool to track candidate drivers of response or resistance to immunotherapies.Third, a genetically engineered mouse model capable of mimicking HCC immune profiles will be generated in this project. Subsequently, mice with different profiles will be exposed to various immunotherapies in order to further explore therapeutic strategies and increase the efficacy of currently available immunotherapies.