title: Expression of RORγt marks a pathogenic regulatory T cell subset in human colon cancer.
abstract: The role of regulatory T cells (T(regs)) in human colon cancer (CC) remains controversial: high densities of tumor-infiltrating T(regs) can correlate with better or worse clinical outcomes depending on the study. In mouse models of cancer, T(regs) have been reported to suppress inflammation and protect the host, suppress T cells and protect the tumor, or even have direct cancer-promoting attributes. These different effects may result from the presence of different T(reg) subsets. We report the preferential expansion of a T(reg) subset in human CC with potent T cell-suppressive, but compromised anti-inflammatory, properties; these cells are distinguished from T(regs) present in healthy donors by their coexpression of Foxp3 and RORγt. T(regs) with similar attributes were found to be expanded in mouse models of hereditary polyposis. Indeed, ablation of the RORγt gene in Foxp3(+) cells in polyp-prone mice stabilized T(reg) anti-inflammatory functions, suppressed inflammation, improved polyp-specific immune surveillance, and severely attenuated polyposis. Ablation of interleukin-6 (IL-6), IL-23, IL-17, or tumor necrosis factor-α in polyp-prone mice reduced polyp number but not to the same extent as loss of RORγt. Surprisingly, loss of IL-17A had a dual effect: IL-17A-deficient mice had fewer polyps but continued to have RORγt(+) T(regs) and developed invasive cancer. Thus, we conclude that RORγt has a central role in determining the balance between protective and pathogenic T(regs) in CC and that T(reg) subtype regulates inflammation, potency of immune surveillance, and severity of disease outcome.
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center, Northwestern University, 303 East Superior Street, Chicago, IL 60611, USA.
authors.forename: Nichole R
authors.initials: NR
authors.lastname: Blatner
authors.forename: Mary F
authors.initials: MF
authors.lastname: Mulcahy
authors.forename: Kristen L
authors.initials: KL
authors.lastname: Dennis
authors.forename: Denise
authors.initials: D
authors.lastname: Scholtens
authors.forename: David J
authors.initials: DJ
authors.lastname: Bentrem
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Phillips
authors.forename: Soo
authors.initials: S
authors.lastname: Ham
authors.forename: Barry P
authors.initials: BP
authors.lastname: Sandall
authors.forename: Mohammad W
authors.initials: MW
authors.lastname: Khan
authors.forename: David M
authors.initials: DM
authors.lastname: Mahvi
authors.forename: Amy L
authors.initials: AL
authors.lastname: Halverson
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Stryker
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Boller
authors.forename: Ashima
authors.initials: A
authors.lastname: Singal
authors.forename: Rebekka K
authors.initials: RK
authors.lastname: Sneed
authors.forename: Bara
authors.initials: B
authors.lastname: Sarraj
authors.forename: Mohammed Javeed
authors.initials: MJ
authors.lastname: Ansari
authors.forename: Martin
authors.initials: M
authors.lastname: Oft
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
authors.forename: Liang
authors.initials: L
authors.lastname: Zhou
authors.forename: Andreas
authors.initials: A
authors.lastname: Bonertz
authors.forename: Philipp
authors.initials: P
authors.lastname: Beckhove
authors.forename: Fotini
authors.initials: F
authors.lastname: Gounari
authors.forename: Khashayarsha
authors.initials: K
authors.lastname: Khazaie
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000378:metabolism; D000818:Animals; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000276:immunology* / Q000473:pathology*; D016207:Cytokines / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D007157:Immunologic Surveillance; D007165:Immunosuppression Therapy; D007249:Inflammation / Q000473:pathology; D007417:Intestinal Polyps / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000172:deficiency / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D016207:Cytokines; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3