title: Tumor-infiltrating plasmacytoid dendritic cells promote immunosuppression by Tr1 cells in human liver tumors.
abstract: CD4+type 1 T regulatory (Tr1) cells have a crucial role in inducing tolerance. Immune regulation by these cells is mainly mediated through the secretion of high amounts of IL-10. Several studies have suggested that this regulatory population may be involved in tumor-mediated immune-suppression. However, direct evidence of a role for Tr1 cells in human solid tumors is lacking. Usingex vivoisolated cells from individuals with hepatocellular carcinoma (HCC;n= 39) or liver metastases from colorectal cancer (LM-CRC;n= 60) we identify a CD4+FoxP3-IL-13-IL-10+T cell population in tumors of individuals with primary or secondary liver cancer that is characterized as Tr1 cells by the expression of CD49b and the lymphocyte activation gene 3 (LAG-3) and strong suppression activity of T cell responses in an IL-10 dependent manner. Importantly, the presence of tumor-infiltrating Tr1 cells is correlated with tumor infiltration of plasmacytoid dendritic cells (pDCs). pDCs exposed to tumor-derived factors enhance IL-10 production by Tr1 cells through up-regulation of the inducible co-stimulatory ligand (ICOS-L). These findings suggest a role for pDCs and ICOS-L in promoting intra-tumoral immunosuppression by Tr1 cells in human liver cancer, which may foster tumor progression and which might interfere with attempts of immunotherapeutic intervention.
authors.affiliation: Department of Gastroenterology and Hepatology; Erasmus MC University Medical Center ; Rotterdam, the Netherlands ; Laboratory of Immunology Research and Medicine; Higher Studies Iztacala; National Autonomous University of Mexico; FES-Iztacala; UNAM , Mexico.
authors.forename: Alexander
authors.initials: A
authors.lastname: Pedroza-Gonzalez
authors.affiliation: Department of Gastroenterology and Hepatology; Erasmus MC University Medical Center ; Rotterdam, the Netherlands.
authors.forename: Guoying
authors.initials: G
authors.lastname: Zhou
authors.affiliation: Department of Gastroenterology and Hepatology; Erasmus MC University Medical Center ; Rotterdam, the Netherlands.
authors.forename: Ernesto
authors.initials: E
authors.lastname: Vargas-Mendez
authors.affiliation: Department of Gastroenterology and Hepatology; Erasmus MC University Medical Center ; Rotterdam, the Netherlands.
authors.forename: Patrick Pc
authors.initials: PP
authors.lastname: Boor
authors.affiliation: Department of Gastroenterology and Hepatology; Erasmus MC University Medical Center ; Rotterdam, the Netherlands.
authors.forename: Shanta
authors.initials: S
authors.lastname: Mancham
authors.affiliation: Department of Surgery; Erasmus MC University Medical Center ; Rotterdam, the Netherlands.
authors.forename: Cornelis
authors.initials: C
authors.lastname: Verhoef
authors.affiliation: Department of Surgery; Erasmus MC University Medical Center ; Rotterdam, the Netherlands.
authors.forename: Wojciech G
authors.initials: WG
authors.lastname: Polak
authors.affiliation: Department of Surgery; Erasmus MC University Medical Center ; Rotterdam, the Netherlands.
authors.forename: Dirk
authors.initials: D
authors.lastname: Grünhagen
authors.affiliation: Department of Gastroenterology and Hepatology; Erasmus MC University Medical Center ; Rotterdam, the Netherlands.
authors.forename: Qiuwei
authors.initials: Q
authors.lastname: Pan
authors.affiliation: Department of Gastroenterology and Hepatology; Erasmus MC University Medical Center ; Rotterdam, the Netherlands.
authors.forename: Harry LA
authors.initials: H
authors.lastname: Janssen
authors.affiliation: Department of Nephrology; Leiden University Medical Center ; Leiden, the Netherlands.
authors.forename: Gina S
authors.initials: GS
authors.lastname: Garcia-Romo
authors.affiliation: Department of Pathology; Erasmus MC-University Medical Center ; Rotterdam, the Netherlands.
authors.forename: Katharina
authors.initials: K
authors.lastname: Biermann
authors.affiliation: Department of Gastroenterology and Hepatology; Erasmus MC University Medical Center ; Rotterdam, the Netherlands.
authors.forename: Eric Ttl
authors.initials: ET
authors.lastname: Tjwa
authors.affiliation: Department of Surgery; Erasmus MC University Medical Center ; Rotterdam, the Netherlands.
authors.forename: Jan Nm
authors.initials: JN
authors.lastname: IJzermans
authors.affiliation: Department of Gastroenterology and Hepatology; Erasmus MC University Medical Center ; Rotterdam, the Netherlands.
authors.forename: Jaap
authors.initials: J
authors.lastname: Kwekkeboom
authors.affiliation: Department of Gastroenterology and Hepatology; Erasmus MC University Medical Center ; Rotterdam, the Netherlands ; Department of Gastroenterology and Hepatology; Academic Medical Center; University of Amsterdam ; the Netherlands.
authors.forename: Dave
authors.initials: D
authors.lastname: Sprengers
keywords: CFSE, carboxyfluorescein diacetate succinimidyl ester; CMV, cytomegalovirus; HCC, hepatocellular carcinoma; ICOS-L; IL-10; Immunotherapy; LM-CRC, liver metastasis from colorectal cancer; TFL, tumor-free area of the liver; TILs, tumor-infiltrating lymphocytes; Tr1 cells; Tr1, CD4+ type 1 T regulatory; colorectal cancer liver metastasis; hepatocellular carcinoma; pDCs, plasmacytoid dendritic cells