TY - JOUR
T1 - Arsenic trioxide exerts antitumor activity through regulatory T cell depletion mediated by oxidative stress in a murine model of colon cancer
AU - Thomas-Schoemann, Audrey
AU - Batteux, Frédéric
AU - Mongaret, Céline
AU - Nicco, Carole
AU - Chéreau, Christiane
AU - Annereau, Maxime
AU - Dauphin, Alain
AU - Goldwasser, François
AU - Weill, Bernard
AU - Lemare, François
AU - Alexandre, Jérôme
PY - 2012/12/1
Y1 - 2012/12/1
N2 - 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 (Treg) numbers. As2O3 induced Treg- 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 Treg count versus controls. As2O3 exerted antitumor effects only in immunocompetent mice and enhanced adoptive immunotherapy effects. Inhibition of As 2O3-induced Treg depletion by the NO synthase inhibitor NG-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 Treg 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 2O3 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.
AB - 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 (Treg) numbers. As2O3 induced Treg- 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 Treg count versus controls. As2O3 exerted antitumor effects only in immunocompetent mice and enhanced adoptive immunotherapy effects. Inhibition of As 2O3-induced Treg depletion by the NO synthase inhibitor NG-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 Treg 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 2O3 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.
UR - http://www.scopus.com/inward/record.url?scp=84869793887&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.1103094
DO - 10.4049/jimmunol.1103094
M3 - Article
C2 - 23105136
AN - SCOPUS:84869793887
SN - 0022-1767
VL - 189
SP - 5171
EP - 5177
JO - Journal of Immunology
JF - Journal of Immunology
IS - 11
ER -