title: Arsenic trioxide exerts antitumor activity through regulatory T cell depletion mediated by oxidative stress in a murine model of colon cancer.
abstract: Immunotherapy is a promising antitumor strategy that can successfully be combined with current anticancer treatment. In this study, arsenic trioxide (As(2)O(3)) was shown to increase the antitumor immune response in CT26 colon tumor-bearing mice through the modulation of regulatory T cell (T(reg)) numbers. As(2)O(3) induced T(reg)-selective depletion in vitro. In vivo, tumor-bearing mice injected with 1 mg/kg As(2)O(3) showed a significant decrease in the T(reg)/CD4 cell ratio and in absolute T(reg) count versus controls. As(2)O(3) exerted antitumor effects only in immunocompetent mice and enhanced adoptive immunotherapy effects. Inhibition of As(2)O(3)-induced T(reg) depletion by the NO synthase inhibitor N(G)-nitro-l-arginine methyl ester and the superoxide dismutase mimic manganese [III] tetrakis-(5, 10, 15, 20)-benzoic acid porphyrin suggested that it was mediated by oxidative and nitrosative stress. The differential effect of As(2)O(3) on T(reg) versus other CD4 cells may be related to differences in the cells' redox status, as indicated by significant differences in 2'7'dichlorodihydrofluorescein diacetate and 4,5-diaminofluorescein diacetate fluorescence levels. In conclusion, these results show for the first time, to our knowledge, that low doses As(2)O(3) can delay solid tumor growth by depleting T(regs) through oxidative and nitrosative bursts, and suggest that As(2)O(3) could be used to enhance the antitumor activity of adoptive immunotherapy strategies in human cancer.
authors.affiliation: Université Paris Descartes, Sorbonne Paris Cité, Unité de Formation et de Recherche des Sciences Pharmaceutiques et Biologiques, 75270 Paris Cedex 06, France. schoemann.audrey@gmail.com
authors.forename: Audrey
authors.initials: A
authors.lastname: Thomas-Schoemann
authors.forename: Frédéric
authors.initials: F
authors.lastname: Batteux
authors.forename: Céline
authors.initials: C
authors.lastname: Mongaret
authors.forename: Carole
authors.initials: C
authors.lastname: Nicco
authors.forename: Christiane
authors.initials: C
authors.lastname: Chéreau
authors.forename: Maxime
authors.initials: M
authors.lastname: Annereau
authors.forename: Alain
authors.initials: A
authors.lastname: Dauphin
authors.forename: François
authors.initials: F
authors.lastname: Goldwasser
authors.forename: Bernard
authors.initials: B
authors.lastname: Weill
authors.forename: François
authors.initials: F
authors.lastname: Lemare
authors.forename: Jérôme
authors.initials: J
authors.lastname: Alexandre
mesh_terms: D000818:Animals; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000637:transplantation; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D019793:Fluorescein; D005452:Fluoresceins; D006801:Humans; D016219:Immunotherapy, Adoptive; D008213:Lymphocyte Activation; D008212:Lymphocyte Depletion; D008665:Metalloporphyrins / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D018384:Oxidative Stress / Q000276:immunology*; D010087:Oxides / Q000494:pharmacology*; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000037:antagonists & inhibitors / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology / Q000473:pathology
chemical_list: C110400:2',7'-dichlorodihydrofluorescein diacetate; C414689:4,5-diaminofluorescein diacetate; D001152:Arsenicals; D004791:Enzyme Inhibitors; D005452:Fluoresceins; D008665:Metalloporphyrins; D010087:Oxides; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; C540743:manganese(III) 5,10,15,20-tetrakis-4-oxy(2-stearic acid)phenylporphyrin; D019001:Nitric Oxide Synthase; D013482:Superoxide Dismutase; D000077237:Arsenic Trioxide; D019793:Fluorescein; D019331:NG-Nitroarginine Methyl Ester