期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2014
卷号：111
期号：49
页码：17582-17587
DOI：10.1073/pnas.1409700111
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceTumor-associated macrophages are often associated with poor prognosis, but the molecular cues that impart the change in macrophage phenotypes are mostly unclear. Our findings identify c-Jun N-terminal phosphorylation as a key mediator of macrophage education and point to a recruitment of immunosuppressive regulatory T cells as a possible effector protumorigenic mechanism. This cross-talk between adaptive and innate immune responses occurs before overt tumorigenesis, reversing the classic paradigm of initiation and promotion. Our findings raise the possibility that targeting immune checkpoints could be effective for tumor prevention in chronic inflammatory diseases. The inflamed tumor microenvironment plays a critical role in tumorigenesis. However, the mechanisms through which immune cells, particularly macrophages, promote tumorigenesis have only been partially elucidated, and the full scope of signaling pathways supplying macrophages with protumorigenic phenotypes still remain largely unknown. Here we report that germ-line absence of c-Jun N-terminal phosphorylation at serines 63 and 73 impedes inflammation-associated hepatocarcinogenesis, yet deleting c-Jun only in hepatocytes does not inhibit hepatocellular carcinoma (HCC) formation. Moreover, in human HCC-bearing livers, c-Jun phosphorylation is found in inflammatory cells, whereas it is mostly absent from malignant hepatocytes. Interestingly, macrophages in livers of mice with chronic hepatitis gradually switch their phenotype along the course of disease. Macrophage phenotype and density are dictated by c-Jun phosphorylation, in vitro and in vivo. Transition of macrophage phenotype, from antitumorigenic to protumorigenic, occurs before tumorigenesis, resulting in the production of various chemokines, including chemokine (C-C motif) ligand 17 (CCL17) and CCL22. Such signals, emanating from the liver microenvironment, direct the recruitment of regulatory T cells, which are known to facilitate HCC growth. Our findings identify c-Jun phosphorylation as a key mediator of macrophage education and point to the recruitment of immunosuppressive regulatory T cells as a possible protumorigenic mechanism.
