title: Hepatic carcinoma-associated fibroblasts induce IDO-producing regulatory dendritic cells through IL-6-mediated STAT3 activation.
abstract: Although carcinoma-associated fibroblasts (CAFs) in tumor microenvironments have a critical role in immune cell modulation, their effects on the generation of regulatory dendritic cells (DCs) are still unclear. In this study, we initially show that CAFs derived from hepatocellular carcinoma (HCC) tumors facilitate the generation of regulatory DCs, which are characterized by low expression of costimulatory molecules, high suppressive cytokines production and enhanced regulation of immune responses, including T-cell proliferation impairment and promotion of regulatory T-cell (Treg) expansion via indoleamine 2,3-dioxygenase (IDO) upregulation. Our findings also indicate that STAT3 activation in DCs, as mediated by CAF-derived interleukin (IL)-6, is essential to IDO production. Moreover, IDO inhibitor, STAT3 and IL-6 blocking antibodies can reverse this hepatic CAF-DC regulatory function. Therefore, our results provide new insights into the mechanisms by which CAFs induce tumor immune escape as well as a novel cancer immunotherapeutic approach (for example, targeting CAFs, IDO or IL-6).
authors.affiliation: Cell-gene Therapy Translational Medicine Research Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.|Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, China.
authors.forename: J-T
authors.initials: JT
authors.lastname: Cheng
authors.affiliation: Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, China.|Department of Hepatic Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
authors.forename: Y-N
authors.initials: YN
authors.lastname: Deng
authors.affiliation: Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, China.|Department of Hepatic Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
authors.forename: H-M
authors.initials: HM
authors.lastname: Yi
authors.affiliation: Department of Hepatic Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
authors.forename: G-Y
authors.initials: GY
authors.lastname: Wang
authors.affiliation: Department of Hepatic Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
authors.forename: B-S
authors.initials: BS
authors.lastname: Fu
authors.affiliation: Cell-gene Therapy Translational Medicine Research Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
authors.forename: W-J
authors.initials: WJ
authors.lastname: Chen
authors.affiliation: Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, China.
authors.forename: W
authors.initials: W
authors.lastname: Liu
authors.affiliation: Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Tai
authors.affiliation: Cell-gene Therapy Translational Medicine Research Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
authors.forename: Y-W
authors.initials: YW
authors.lastname: Peng
authors.affiliation: Cell-gene Therapy Translational Medicine Research Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.|Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Zhang