Demethylating agent decitabine disrupts tumor-induced immune tolerance by depleting myeloid-derived suppressor cells.
OBJECTIVE
The immunoregulatory effect of demethylating agent decitabine (DAC) has been recognized recently. However, little is known about its impact on immune tolerance. In this study, we aimed to determine the impact of DAC on the immune tolerance induced by tumor cells.


METHODS
The effects of DAC on immune cells in vivo were measured by flow cytometry. Myeloid-derived suppressor cells (MDSCs) were sorted using magnetic beads and cultured in vitro. The mixed lymphocyte reaction was used to determine the immunoregulatory effect of DAC in vitro. An adoptive transfusion mouse model was established to evaluate the effect in vivo.


RESULTS
We found that DAC treatment significantly depleted MDSCs in vivo by inducing MDSCs apoptosis. When given at a low dose, the immune effector cells were less affected by the treatment, except for MDSCs. The mixed lymphocyte reaction in vitro showed that T-cell responses were enhanced when MDSCs were depleted. Supplementation of MDSCs would attenuate this T-cell activation effect. Using an adoptive transfusion mouse model, we further demonstrated in vivo that DAC treatment could induce autologous anti-tumor immune response by depleting MDSCs.


CONCLUSIONS
This study is the first to illustrate DAC's immunoregulatory effect on immune tolerance. The disruption of immune tolerance is due to MDSCs depletion that induces an autologous immune response in vivo. By depleting MDSCs, DAC treatment removes one of the obstacles affecting anti-tumor immune activation and warrants further experimental and clinical studies to explore its potential utility in combination with various anti-tumor immunotherapies in the future.
Department of Hematology, The Second Clinical Medical College (Shenzhen People's Hospital), Jinan University, 1017 Dongmen North Road, Shenzhen, 518020, Guangdong Province, People's Republic of China.
Jihao
J
Zhou
McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada.
Yushi
Y
Yao
Department of Hematology, The Second Clinical Medical College (Shenzhen People's Hospital), Jinan University, 1017 Dongmen North Road, Shenzhen, 518020, Guangdong Province, People's Republic of China.
Qi
Q
Shen
Department of Hematology, The Second Clinical Medical College (Shenzhen People's Hospital), Jinan University, 1017 Dongmen North Road, Shenzhen, 518020, Guangdong Province, People's Republic of China.
Guoqiang
G
Li
Department of Hematology, The Second Clinical Medical College (Shenzhen People's Hospital), Jinan University, 1017 Dongmen North Road, Shenzhen, 518020, Guangdong Province, People's Republic of China.
Lina
L
Hu
Department of Hematology, The Second Clinical Medical College (Shenzhen People's Hospital), Jinan University, 1017 Dongmen North Road, Shenzhen, 518020, Guangdong Province, People's Republic of China. zhangxinyou0518@sina.com.
Xinyou
X
Zhang
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001374:Azacitidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D045744:Cell Line, Tumor; D000077209:Decitabine; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects*; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D000072737:Myeloid-Derived Suppressor Cells / Q000187:drug effects / Q000276:immunology; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
D000077209:Decitabine; D001374:Azacitidine
Decitabine; Demethylation; Immune tolerance; Immunotherapy; Myeloid-derived suppressor cells