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

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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.