title: Blockade of TNF-α signaling benefits cancer therapy by suppressing effector regulatory T cell expansion.
abstract: Effector but not naive regulatory T cells (Treg cells) can accumulate in the peripheral blood as well as the tumor microenvironment, expand during tumor progression and be one of the main suppressors for antitumor immunity. However, the underlying mechanisms for effector Treg cell expansion in tumor are still unknown. We demonstrate that effector Treg cell-mediated suppression of antitumor CD8+T cells is tumor-nonspecific. Furthermore, TNFR2 expression is increased in these Treg cells by Affymetrix chip analysis which was confirmed by monoclonal antibody staining in both hepatocellular carcinoma (HCC) and colorectal cancer (CRC) patients and murine models. Correspondingly, increased levels of TNF-α in both tissue and serum were also demonstrated. Interestingly, TNF-α could not only expand effector Treg cells through TNFR2 signaling, but also enhanced their suppressive activity against antitumor immunity of CD8+T cells. Furthermore, targeting TNFR2 signaling with a TNF-α inhibitor could selectively reduce rapid resurgence of effector Treg cells after cyclophosphamide-induced lymphodepletion and markedly inhibit the growth of established tumors. Herein, we propose a novel mechanism in which TNF-α could promote tumor-associated effector Treg cell expansion and suggest a new cancer immunotherapy strategy using TNF-α inhibitors to reduce effector Treg cells expansion after cyclophosphamide-induced lymphodepletion.
authors.affiliation: Division of Hepatology; Department of Gastroenterology and Hepatology; Linkou Medical Center; Chang Gung Memorial Hospital ; Kweishan, Taoyuan, Taiwan.
authors.forename: Li-Yuan
authors.initials: LY
authors.lastname: Chang
authors.affiliation: College of Medicine; Chang Gung University ; Kweishan, Taoyuan, Taiwan ; Department of Hematology/Oncology; Linkou Medical Center; Chang Gung Memorial Hospital ; Kweishan, Taoyuan, Taiwan.
authors.forename: Yung-Chang
authors.initials: YC
authors.lastname: Lin
authors.affiliation: College of Medicine; Chang Gung University ; Kweishan, Taoyuan, Taiwan ; Colorectal Surgery Section; Department of Surgery; Linkou Medical Center; Chang Gung Memorial Hospital ; Kweishan, Taoyuan, Taiwan.
authors.forename: Jy-Ming
authors.initials: JM
authors.lastname: Chiang
authors.affiliation: Division of Hepatology; Department of Gastroenterology and Hepatology; Linkou Medical Center; Chang Gung Memorial Hospital ; Kweishan, Taoyuan, Taiwan.
authors.forename: Jayashri
authors.initials: J
authors.lastname: Mahalingam
authors.affiliation: College of Medicine; Chang Gung University ; Kweishan, Taoyuan, Taiwan.
authors.forename: Shih-Huan
authors.initials: SH
authors.lastname: Su
authors.affiliation: College of Medicine; Chang Gung University ; Kweishan, Taoyuan, Taiwan ; Department of Infectious Disease; Linkou Medical Center; Chang Gung Memorial Hospital ; Kweishan, Taoyuan, Taiwan.
authors.forename: Ching-Tai
authors.initials: CT
authors.lastname: Huang
authors.affiliation: Division of Hepatology; Department of Gastroenterology and Hepatology; Linkou Medical Center; Chang Gung Memorial Hospital ; Kweishan, Taoyuan, Taiwan ; College of Medicine; Chang Gung University ; Kweishan, Taoyuan, Taiwan.
authors.forename: Wei-Ting
authors.initials: WT
authors.lastname: Chen
authors.affiliation: Division of Hepatology; Department of Gastroenterology and Hepatology; Linkou Medical Center; Chang Gung Memorial Hospital ; Kweishan, Taoyuan, Taiwan.
authors.forename: Chien-Hao
authors.initials: CH
authors.lastname: Huang
authors.affiliation: Division of Hepatology; Department of Gastroenterology and Hepatology; Linkou Medical Center; Chang Gung Memorial Hospital ; Kweishan, Taoyuan, Taiwan.
authors.forename: Wen-Juei
authors.initials: WJ
authors.lastname: Jeng
authors.affiliation: Division of Hepatology; Department of Gastroenterology and Hepatology; Linkou Medical Center; Chang Gung Memorial Hospital ; Kweishan, Taoyuan, Taiwan ; College of Medicine; Chang Gung University ; Kweishan, Taoyuan, Taiwan.
authors.forename: Yi-Cheng
authors.initials: YC
authors.lastname: Chen
authors.affiliation: Division of Hepatology; Department of Gastroenterology and Hepatology; Linkou Medical Center; Chang Gung Memorial Hospital ; Kweishan, Taoyuan, Taiwan ; College of Medicine; Chang Gung University ; Kweishan, Taoyuan, Taiwan.
authors.forename: Shi-Ming
authors.initials: SM
authors.lastname: Lin
authors.affiliation: Division of Hepatology; Department of Gastroenterology and Hepatology; Linkou Medical Center; Chang Gung Memorial Hospital ; Kweishan, Taoyuan, Taiwan ; College of Medicine; Chang Gung University ; Kweishan, Taoyuan, Taiwan.
authors.forename: I-Shyan
authors.initials: IS
authors.lastname: Sheen
authors.affiliation: Division of Hepatology; Department of Gastroenterology and Hepatology; Linkou Medical Center; Chang Gung Memorial Hospital ; Kweishan, Taoyuan, Taiwan ; College of Medicine; Chang Gung University ; Kweishan, Taoyuan, Taiwan.
authors.forename: Chun-Yen
authors.initials: CY
authors.lastname: Lin
keywords: TNF-α; TNFR2; colorectal cancer; cyclophosphamide; effector regulatory T cells; hepatocellular carcinoma