title: Instability of Helios-deficient Tregs is associated with conversion to a T-effector phenotype and enhanced antitumor immunity.
abstract: Expression of the transcription factor Helios by Tregs ensures stable expression of a suppressive and anergic phenotype in the face of intense inflammatory responses, whereas Helios-deficient Tregs display diminished lineage stability, reduced FoxP3 expression, and production of proinflammatory cytokines. Here we report that selective Helios deficiency within CD4 Tregs leads to enhanced antitumor immunity through induction of an unstable phenotype and conversion of intratumoral Tregs into T effector cells within the tumor microenvironment. Induction of an unstable Treg phenotype is associated with enhanced production of proinflammatory cytokines by tumor-infiltrating but not systemic Tregs and significantly delayed tumor growth. Ab-dependent engagement of Treg surface receptors that result in Helios down-regulation also promotes conversion of intratumoral but not systemic Tregs into T effector cells and leads to enhanced antitumor immunity. These findings suggest that selective instability and conversion of intratumoral CD4 Tregs through genetic or Ab-based targeting of Helios may represent an effective approach to immunotherapy.
authors.affiliation: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215; Department of Microbiology and Immunobiology, Division of Immunology, Harvard Medical School, Boston, MA 02115.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Nakagawa
authors.affiliation: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215; Department of Microbiology and Immunobiology, Division of Immunology, Harvard Medical School, Boston, MA 02115.
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Sido
authors.affiliation: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215; Department of Microbiology and Immunobiology, Division of Immunology, Harvard Medical School, Boston, MA 02115.
authors.forename: Edwin E
authors.initials: EE
authors.lastname: Reyes
authors.affiliation: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215;
authors.forename: Valerie
authors.initials: V
authors.lastname: Kiers
authors.affiliation: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215; Department of Microbiology and Immunobiology, Division of Immunology, Harvard Medical School, Boston, MA 02115 Hye-Jung_Kim@dfci.harvard.edu harvey_cantor@dfci.harvard.edu.
authors.forename: Harvey
authors.initials: H
authors.lastname: Cantor
authors.affiliation: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215; Department of Microbiology and Immunobiology, Division of Immunology, Harvard Medical School, Boston, MA 02115 Hye-Jung_Kim@dfci.harvard.edu harvey_cantor@dfci.harvard.edu.
authors.forename: Hye-Jung
authors.initials: HJ
authors.lastname: Kim
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000502:physiology*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology* / Q000378:metabolism; D008546:Melanoma, Experimental / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D018345:Mice, Knockout; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D014157:Transcription Factors / Q000502:physiology*
chemical_list: D004268:DNA-Binding Proteins; D011948:Receptors, Antigen, T-Cell; D014157:Transcription Factors; C491746:Zfpn1a2 protein, mouse
keywords: Treg stability; effector cytokines; inflammation; tumor microenvironment