NCR−ILC3 as the initial responders to liver inflammatory environment promote HCC development through IL-23/IL-17 axis

Abstract

Abstract IL-17 is crucial in tumor-promoting inflammation and the development of hepatocellular carcinoma (HCC). However, the role of IL-23, an important IL-17-inducing inflammatory cytokine, as well as the immune cells responsible for initiating IL-17 production in the tumor microenvironment are not clear. In the current study, we assessed the development of HCC and the function of the adaptive anti-tumor immune response, as well as the kinetics of the development of IL-17-producing cells in an IL-23-rich tumor microenvironment. Our results demonstrated that IL-23 promoted HCC tumor growth and inhibited anti-tumor adaptive immune response by enhancing IL-17A production in the tumor microenvironment. Furthermore, our kinetic analysis showed that NCR−ILC3 were the first responders to IL-23, producing IL-17 during the early phase of tumor development. Their proliferation in vivo was facilitated by IL-23, and adoptive transfer of NCR−ILC3 cells promoted HCC development. NCR−ILC3 could suppress IFN-γ production of both CD4+ and CD8+ T cells, and inhibit proliferation and survival of CD8+ T cells in vitro. Moreover, the percentage of IFN-γ-producing ILC1 were significantly reduced by IL-23 in the liver during tumor development, and they were shown to be able to differentiate into ILC3 in the presence of IL-1β and/or IL-23 in vitro. The adoptive transfer experiment further demonstrated that ILC1 could gain RORγt expression in an IL-23-expressing HCC model. Therefore, our findings demonstrated that IL-23 could promote HCC development through enhancing IL-17 production, and NCR−ILC3 as the initial IL-17-producing cells in response to IL-23 in the liver could be the initiator of the IL-17-rich immune-suppressive tumor microenvironment.