Targeted inhibition of myeloid-derived suppressor cells in the tumor microenvironment by low-dose doxorubicin to improve immune efficacy in murine neuroblastoma.
10.1097/CM9.0000000000001234
- Author:
Wei-Li XU
1
;
Bao-Jun SHI
1
;
Suo-Lin LI
1
;
Feng-Xue YU
2
;
Li-Na GUO
2
;
Meng LI
1
;
Zhi-Gang HU
3
;
Gui-Xin LI
3
;
Hui ZHOU
1
Author Information
1. Department of Pediatric Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, China.
2. Department of Central Laboratory, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, China.
3. Department of General Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, China.
- Publication Type:Journal Article
- MeSH:
Animals;
Doxorubicin/therapeutic use*;
Mice;
Mice, Inbred C57BL;
Myeloid-Derived Suppressor Cells;
Neuroblastoma/drug therapy*;
Tumor Microenvironment
- From:
Chinese Medical Journal
2020;134(3):334-343
- CountryChina
- Language:English
-
Abstract:
BACKGROUND:High agglomeration of myeloid-derived suppressor cells (MDSCs) in neuroblastoma (NB) impeded therapeutic effects. This study aimed to investigate the role and mechanism of targeted inhibition of MDSCs by low-dose doxorubicin (DOX) to enhance immune efficacy in NB.
METHODS:Bagg albino (BALB/c) mice were used as tumor-bearing mouse models by injecting Neuro-2a cells, and MDSCs were eliminated by DOX or dopamine (DA) administration. Tumor-bearing mice were randomly divided into 2.5 mg/kg DOX, 5.0 mg/kg DOX, 50.0 mg/kg DA, and control groups (n = 20). The optimal drug and its concentration for MDSC inhibition were selected according to tumor inhibition. NB antigen-specific cytotoxic T cells (CTLs) were prepared. Tumor-bearing mice were randomly divided into DOX, CTL, anti-ganglioside (GD2), DOX+CTL, DOX+anti-GD2, and control groups. Following low-dose DOX administration, immunotherapy was applied. The levels of human leukocyte antigen (HLA)-I, CD8, interleukin (IL)-2 and interferon (IFN)-γ in peripheral blood, CTLs, T-helper 1 (Thl)/Th2 cytokines, perforin, granzyme and tumor growth were compared among the groups. The Wilcoxon two-sample test and repeated-measures analysis of variance were used to analyze results.
RESULTS:The slowest tumor growth (F = 6.095, P = 0.018) and strongest MDSC inhibition (F = 14.632, P = 0.001) were observed in 2.5 mg/kg DOX group. Proliferation of T cells was increased (F = 448.721, P < 0.001) and then decreased (F = 2.047, P = 0.186). After low-dose DOX administration, HLA-I (F = 222.489), CD8 (F = 271.686), Thl/Th2 cytokines, CD4+ and CD8+ lymphocytes, granzyme (F = 2376.475) and perforin (F = 488.531) in tumor, IL-2 (F = 62.951) and IFN-γ (F = 240.709) in peripheral blood of each immunotherapy group were all higher compared with the control group (all of P values < 0.05). The most significant increases in the aforementioned indexes and the most notable tumor growth inhibition were observed in DOX+anti-GD2 and DOX+CTL groups.
CONCLUSIONS:Low-dose DOX can be used as a potent immunomodulatory agent that selectively impairs MDSC-induced immunosuppression, thereby fostering immune efficacy in NB.
