Project 3: Chronic interferon and bile acid signaling as drivers of immunosuppression in age-related liver cancer

项目摘要--项目3 肝癌是全球癌症相关死亡的主要原因(1，2)。年龄是一种致命的风险 癌症--60岁以上的人更容易患上原发性肝癌(3)。老龄化的一个关键方面 这个过程是慢性炎症的发展，抑制了体内平衡的肝脏功能，从而 促进肿瘤生长(4，5)。具体地说，我们主张在衰老过程中，慢性干扰素(干扰素)信号 导致肝细胞和免疫细胞中抑制抗肿瘤的免疫检查点上调 免疫反应。除了上调免疫检查点外，慢性干扰素信号还可诱导多种 代谢紊乱可能共同作用，抑制抗肿瘤免疫反应。胆汁酸(BA)是 在这方面要考虑重要的代谢物，因为bas在肝脏内的积累是一个重要的 可能导致肝肿瘤发生和发展的危险因素(6，7)。而肝癌通常是 被T细胞渗透，令人惊讶的是，这种类型的肿瘤对免疫检查点阻断和 过继T细胞治疗(8，9)。我们的初步分析表明，bas随着年龄的增长而积累，我们假设 过量的bas可导致对浸润性T细胞和定向T细胞的抑制 抗击肝癌的免疫疗法。BA信号对T细胞功能的直接抑制作用，尤其是在 到目前为止，抗肿瘤免疫的背景还没有得到很好的研究。因此，我们计划通过以下方式来研究新方法 哪些持续的BA信号影响肿瘤内T细胞的抑制，尤其是对这种抑制的剖析 衰老的机制，因为它与肿瘤进展有关。代谢物，如bas，在体内积聚 在衰老过程中，肝脏可以与其他抑制分子一起起作用，例如干扰素导向的免疫。 像PD-L1这样的检查点，促进T细胞功能障碍。这个在老龄化和癌症的交界处的项目有很大的 有可能提供新的和有效的方法来恢复CD8T细胞介导的免疫，从而提供新的 预防和治疗侵袭性癌症的途径，包括结肠癌、食道癌和胰腺癌 BAS可以积聚并参与疾病的发病机制(10)。此外，该项目将利用 冯博士(项目4)在BA信号和肝癌小鼠模型方面的专业知识，Shadel博士(项目1)在 代谢和线粒体功能及干扰素信号和衰老机制，亚当斯博士(项目2) 对于小鼠衰老模型和衰老相关基因表达的变化，萨科博士(Core B)针对所有主要小鼠 模型和常见干预措施，以及Shokhirev博士(核心C)，用于生物信息学和系统层面的分析 与年龄相关的肝脏变化和肿瘤进展。

PROJECT SUMMARY – PROJECT 3 Liver cancer is a leading cause of cancer related deaths world-wide (1,2). Age is a crucial risk for acquiring cancer as people older than 60 are more likely to develop primary liver cancer (3). A key aspect of the aging process is the development of chronic inflammation that inhibits the homeostatic liver functions, thereby contributing to tumor growth (4,5). Specifically, we advocate that during aging, chronic interferon (IFN) signaling leads to upregulation of immune checkpoints in both hepatocytes and immune cells that suppress anti-tumor immune responses. Besides upregulating immune checkpoints, chronic IFN signaling also induces various metabolic disruptions that could act together to inhibit anti-tumor immune responses. Bile acids (BAs) are important metabolites to consider in this regard, because the accumulation of BAs within the liver is an important risk factor that could contribute to liver tumor initiation and progression (6,7). While liver cancers are often infiltrated by T cells, surprisingly, this type of tumor is fairly unresponsive to immune-checkpoint blockade and adoptive T cell therapy (8,9). Our preliminary analysis shows that BAs accumulate with age, and we hypothesize that such excessive amount of BAs could cause suppression of infiltrating T cells and T cell directed immunotherapies to combat liver cancer. A direct inhibitory role for BA signaling on T-cell function, especially in the context of anti-tumor immunity, has not been well-investigated to date. Thus, we plan to study novel ways by which persistent BA signaling influences T cell suppression within tumors, notably dissecting such suppressive mechanisms in the context of aging as it relates to tumor progression. Metabolites such as BAs that build-up in the liver during aging can act together with other inhibitory molecules, for example IFN-directed immune checkpoints like PD-L1, to promote T cell dysfunction. This project at the interface of aging and cancer has great potential to provide new and efficient ways to rejuvenate CD8+ T cell mediated immunity, thereby providing novel avenues to prevent and treat aggressive cancers including colon, esophageal and pancreatic cancers for which BAs can accumulate and contribute to disease pathogenesis (10). Moreover, this Project will leverage the expertise of Dr. Feng (Project 4) for BA-signaling and liver cancer mouse models, Dr. Shadel (Project 1) for metabolic and mitochondrial function and mechanisms of IFN-signaling and aging, and Dr. Adams (Project 2) for mouse models of aging and age-related changes in gene expression, Dr. Sacco (Core B) for all major mouse models and common interventions, and Dr. Shokhirev (Core C) for bioinformatic and systems-level analyses of age related changes in the liver and tumor progression.