Research Project
10270689
PROJECT SUMMARY ? PROJECT 4 Primary liver cancer, mainly hepatocellular carcinoma (HCC), is now one of the most deadly malignant diseases. Aging is a high-risk factor for HCC development, although the underlying mechanisms are poorly understood. The aging liver is characterized by progressive development of an immunosuppressive microenvironment, contributed by chronic interferon (IFN) signaling, metabolic changes and altered innate and adaptive immunity. Thus, liver tumors are poorly responsive to immunotherapy. The goal of project 4 is to elucidate the roles of IFN and other inflammatory cytokines in aging-related changes of the hepatic immunological landscape. This project was prompted by our unexpected finding in most recent experiments. In dissecting molecular mechanisms of liver tumorigenesis with an inducible gene targeting system, Mx1-cre, we identified a robust tumor-inhibitory effect of polyinosinic-polycytidylic acid (polyIC), a synthetic dsRNA that induces IFN expression. These data on IFN signaling not only challenge a widely known theory of IL1a-IL6 cytokine circuit in liver tumorigenesis, but also open up new strategies for HCC immunotherapy. However, preliminary data also showed that injecting polyIC into aged mice triggered sharply different immune responses and actually aggravated HCC progression if given at late tumor stages. Thus, we hypothesize that IFN and other related inflammatory cytokines have bidirectional or paradoxical roles in HCC development, depending on ages and tumor stages. To test this hypothesis, we will extensively interrogate the roles of IFN signaling in a NASH-HCC model at single cell resolution. We will also further develop and optimize a math model and a TI (tumorigenic index) calculation system to quantitatively measure tumorigenic signal strength, tumor stages and prognosis, and also evaluate tumor-inhibitory effects of various manipulation or treatment strategies. Of note, preliminary data also showed robust induction of PD-L1 expression by polyIC in the liver, which prompted us to test a combination of polyIC and PD-L1/PD-1 blockade in treatment of liver cancer in young and old mice. We shall extensively investigate how coordinated activation of innate and adaptive immune functions can effectively suppress primary and metastatic tumor progression in the liver. Finally, we shall take advantage of newly established mouse tumor models, to systematically search for liver-specific factors and mechanisms of resistance to immunotherapy. All of the proposed experiments in this ambitious project can only be done in collaboration with Shadel, Adams and Kaech with complementary expertise and the Cores.
