title: GITR engagement in combination with CTLA-4 blockade completely abrogates immunosuppression mediated by human liver tumor-derived regulatory T cellsex vivo.
abstract: In liver cancer tumor-infiltrating regulatory T cells (Ti-Treg) are potent suppressors of tumor-specific T-cell responses and express high levels of the Treg-associated molecules cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and glucocorticoid-induced tumor necrosis factor receptor (GITR). In this study, we have evaluated the capacity of GITR-ligation, CTLA-4-blockade and a combination of both treatments to alleviate immunosuppression mediated by Ti-Treg. Usingex vivoisolated cells from individuals with hepatocellular carcinoma (HCC) or liver metastases from colorectal cancer (LM-CRC) we show that treatment with a soluble form of the natural ligand of GITR (GITRL), or with blocking antibodies to CTLA-4, reduces the suppression mediated by human liver tumor-infiltrating CD4+Foxp3+ Treg, thereby restoring proliferation and cytokine production by effector T cells. Importantly, combined treatment with low doses of both molecules exhibited stronger recovery of T cell function compared with either treatment alone. Our data suggest that in patients with primary and secondary liver cancer both GITR-ligation and anti-CTLA-4 mAb can improve the antitumor immunity by abrogating Ti-Treg mediated suppression.
authors.affiliation: Department of Gastroenterology and Hepatology; Erasmus MC University Medical Center ; Rotterdam, The Netherlands ; Laboratory of Immunology Research, Medicine; Faculty of Higher Studies Iztacala; National Autonomous University of Mexico; FES-Iztacala, UNAM ; Mexico City, 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: Simar Pal
authors.initials: SP
authors.lastname: Singh
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: Qiuwei
authors.initials: Q
authors.lastname: Pan
authors.affiliation: Department of Surgery; Erasmus MC University Medical Center ; Rotterdam, The Netherlands.
authors.forename: Dirk
authors.initials: D
authors.lastname: Grunhagen
authors.affiliation: Department of Surgery; Erasmus MC University Medical Center ; Rotterdam, The Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: de Jonge
authors.affiliation: Department of Surgery; Erasmus MC University Medical Center ; Rotterdam, The Netherlands.
authors.forename: Tc Khe
authors.initials: TK
authors.lastname: Tran
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: 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: Harry LA
authors.initials: H
authors.lastname: Janssen
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: Jaap
authors.initials: J
authors.lastname: Kwekkeboom
authors.affiliation: Department of Gastroenterology and Hepatology; Erasmus MC University Medical Center ; Rotterdam, The Netherlands.
authors.forename: Dave
authors.initials: D
authors.lastname: Sprengers
keywords: cytotoxic T lymphocyte-associated antigen 4 (CTLA-4); glucocorticoid-induced tumor necrosis factor receptor (GITR); hepatocellular carcinoma (HCC); liver metastases from colorectal cancer (LM-CRC); regulatory T cells (Treg)