Abstract
Purpose
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.
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Abbreviations
- DAC:
-
Decitabine
- MDSCs:
-
Myeloid-derived suppressor cells
- CTA:
-
Cancer-testis antigens
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Acknowledgements
This work was supported by the National Natural Science Foundation of China (No. 81600168) and the Basic Research Project of Shenzhen Science and Technology Program (No. JCYJ20160422145031770). We thank Dr. Lixin Wang (Department of Hematology, Navy General Hospital, Beijing, China) and Prof. Li Yu (Department of Hematology, PLA General Hospital, Beijing, China) for helpful discussions and support to this study.
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This study was funded by the National Natural Science Foundation of China (Grant No. 81600168) and the Basic Research Project of Shenzhen Science and Technology Program (Grant No. JCYJ20160422145031770).
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Author Jihao Zhou declares that he has no conflict of interest. Author Yushi Yao declares that he has no conflict of interest. Author Qi Shen declares that she has no conflict of interest. Author Guoqiang Li declares that he has no conflict of interest. Author Lina Hu declares that she has no conflict of interest. Author Xinyou Zhang declares that he has no conflict of interest.
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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. This article does not contain any studies with human participants performed by any of the authors.
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Zhou, J., Yao, Y., Shen, Q. et al. Demethylating agent decitabine disrupts tumor-induced immune tolerance by depleting myeloid-derived suppressor cells. J Cancer Res Clin Oncol 143, 1371–1380 (2017). https://doi.org/10.1007/s00432-017-2394-6
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DOI: https://doi.org/10.1007/s00432-017-2394-6