Arsenic Trioxide Exerts Antitumor Activity through Regulatory T Cell Depletion Mediated by Oxidative Stress in a Murine Model of Colon Cancer

Immunotherapy is a promising antitumor strategy that can successfully be combined with current anticancer treatment. In this study, arsenic trioxide (As2O3) was shown to increase the antitumor immune response in CT26 colon tumor-bearing mice through the modulation of regulatory T cell (T-reg) numbers. As2O3 induced T-reg-selective depletion in vitro. In vivo, tumor-bearing mice injected with 1 mg/kg As2O3 showed a significant decrease in the T-reg/CD4 cell ratio and in absolute T-reg count versus controls. As2O3 exerted antitumor effects only in immunocompetent mice and enhanced adoptive immunotherapy effects. Inhibition of As2O3-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 As2O3 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 As2O3 can delay solid tumor growth by depleting T-regs through oxidative and nitrosative bursts, and suggest that As2O3 could be used to enhance the antitumor activity of adoptive immunotherapy strategies in human cancer. The Journal of Immunology, 2012, 189: 5171-5177.