肠道微生态依赖的白介素-24在肥胖相关肝癌微环境中的作用及机制研究

Obesity facilitates the generation and progression of a variety of malignant tumors, including hepatocellular carcinoma (HCC), yet its regulation on tumor immunity has not been mechanistically defined. As indicated in our preliminary work, the number of regulatory B cells (Breg) was markedly increased in the obesity-shaped HCC microenvironment; moreover, among diverse obesity-assocoated inflammatory factors, the level of interleukin-20 (IL-20) family member IL-24 was specifically down-modulated. In the present study, we aim to seek the functional roles of type II cytokines including IL-24 involved in the obesity-educated HCC microenvironment, regarding their regulation on B cell immunity. Since obesity edits gut microbiota, we intend to clarify the cell source of IL-24 and identify its upstream signals from the perspective of gut microenvironment. Group 2 innate lymphoid cells (ILC2) are an obesity-and-microbe-sensitive subset of innate immune cells, which will be explored in the enterohepatic cycle. Thereby, we may investigate their production of type II cytokines including IL-24 and function on the obesity-shaped HCC immunity. At the interface of metabolism, gut microbiota and tumor immunity, we exploit the potentially key mediator IL-24 to understand how obesity results in tumor immunotolerance, which may provide the molecular target and insight to the precision medicine based tumor immunotherapy.

肥胖可促进肝细胞肝癌(HCC)等恶性肿瘤的发生及进展，然而其对肿瘤免疫的调控作用和机理并不十分明确。我们的预实验结果显示，肥胖机体HCC微环境中调节性B细胞(Breg)的数量显著增加；在众多肥胖相关炎症因子中, 白介素-20 (IL-20)家族成员IL-24可发生特异性表达下调。本项目将立足于肥胖相关HCC微环境，探讨IL-24等II型细胞因子对B细胞肿瘤免疫的调控作用；鉴于肥胖可重塑肠道微生态，我们将从肠道微环境的视角，阐述IL-24的细胞来源及其受到的信号调控。第二类固有淋巴细胞(ILC2)是一群肥胖/微生物敏感性先天免疫细胞，我们将分析其在肠肝循环中对IL-24等II型细胞因子的分泌及在肥胖相关HCC微环境中的功能。着眼于 “代谢-微生物-免疫”信号网络，我们将解析IL-24这一潜在的关键节点，从而阐明肥胖调控肿瘤免疫耐受的机理，以期为精准肿瘤免疫治疗提供分子靶点及理论依据。

本项目着眼于肝脏炎症、免疫及肿瘤微环境，鉴定并探讨了IL-24作为肝细胞内质网锚定蛋白的免疫生物学作用。一方面，我们发现IL-24可抑制炎性肝细胞损伤及肝细胞肝癌发生、进展的重要功能；另一方面，我们发现IL-24可在肝细胞内质网表面与核糖体互作，指导蛋白翻译及转运，从而间接促进抗肿瘤免疫。. 发现肝细胞内IL-24可通过控制内质网应激抑制炎性肝脏损伤的进展。肝细胞内质网应激或急性肝损伤时，肝细胞IL-24表达可一过性增加。肝细胞IL-24的缺失会导致肝细胞内质网应激性死亡，从而促进急性肝损伤。肝细胞IL-24通过抑制PERK-eIF2α-CHOP通路的持续激活从而减轻肝损伤。不仅如此，急性肝衰竭患者表现出肝脏IL-24表达的显著降低，其水平与疾病进展呈负相关（Cell Death & Disease 2020;11(1):17 (IF: 6.304)）。.发现肝细胞内IL-24介导的内质网稳态可维持肝脏抗肿瘤免疫。肝细胞高表达IL-24的肝癌病人预后较好，且其表达水平与多种免疫细胞浸润及免疫活化信号呈正相关。IL-24缺失小鼠具有肝脏特异性的肿瘤免疫缺陷，显著促进肝内肿瘤进展。肿瘤负荷下，肝细胞IL-24可与核糖体eIF5蛋白发生特异性结合，从而调控关键蛋白的翻译和转运；后者可通过抑制B细胞的髓细胞样表型及Mincle分子表达间接促进抗肿瘤免疫（暂未发表）。. 在本项目支持下，负责人同时致力于肝肿瘤免疫调节的理论研究及转化探索。以第一作者提出免疫抑制性细胞死亡的概念，发表于Nature Reviews Immunology.2017;17(6):401(IF: 40.358)；完成首篇“肝癌免疫生物学”综述, 发表于Journal of Hepatology 2020;72(1):167-182 (IF: 20.582)；近期受邀于Nature Reviews Clinical Oncology(IF: 53.276)杂志，以第一作者完成“肿瘤相关性炎症靶向治疗”的综述。. 上述研究工作对完善肝肿瘤免疫生物学理论体系及推动肝肿瘤精准免疫治疗具有重要意义。