Weili Xu

and 5 more

Background High agglomeration of myeloid-derived suppressor cell (MDSC) in tumor microenvironment resulted in immune escape and affected therapeutic effects. Doxorubicin (DOX) or dopamine (DA) is found the specific drug to selectively remove or maturate MDSC. How to effectively eliminate MDSC in neuroblastoma (NB) and its mechanism need to be clarified. Procedure In the present study, BALB/c tumor-bearing mice model were established by NB cells injection, then grouped into DOX2.5 mg/kg group, DOX5 mg/kg group, DA50 mg/kg group and control group. DOX or DA were injected intravenously in advance, then quantity and distribution of MDSC, proliferation and infiltration of T cell, Treg level and TAM polarization, MDSC related functional molecules in vivo and expression of proteins in signal transducer and activator of transcription (STAT) pathway in MDSC were detected and compared respectively at 14 d, 17 d and 23 d after inoculation. The tumor growth were compared between the groups. Results After DOX or DA administration, in each experimental group, MDSC ratio all decreased. STAT1, p-STAT1 and activated caspase-3 decreased, but STAT3, p-STAT3, STAT5, p-STAT5, STAT6, p-STAT6, Arg-1 and IDO increased. Simutaneously, compared with the control group, T cell proliferation in tumor first increased and then inhibited, infiltration of T cells increased, TAM polarization and Treg level reduced, the tumor growth was inhibited. Changes in above indicators were most significant in DOX2.5mg/kg group. Conclusions Low-dose DOX administration can eliminate MDSC in NB by regulating STAT signaling pathway in MDSC, thus remove immunosuppression and improve immune efficacy of NB.

Weili Xu

and 5 more

Background High agglomeration of myeloid-derived suppressor cell (MDSC) in neuroblastoma (NB) resulted in immune tolerance and impeded therapeutic effects. Doxorubicin (DOX) is currently found the most specific drug to selectively remove MDSC. However, whether these mechanisms can relieve the inhibitory role of MDSC in NB immunotherapy is still remain unclear. Procedure In this study, the inhibitory role of MDSC for NB Ag-specific cytotoxic T lymphocyte (CTL) were investigated in vitro. CTLs, NB cells, MDSCs and DOX were mixed and cultivated in different collocation pattern, the levels of cluster of differentiation 3ζ chain (CD3ζ) and L-selectin in CTL in different groups were detected. Thereafter, the killing rate of neuroblastoma cells, secretion of interleukin-2 and interferon-γ were detected and compared. Results The proliferation and killing effect of CTLs on neuroblastoma cells were all inhibited by MDSC through downregulating CD3ζ (P = 0.002; P = 0.001) and L-selectin (P = 0.006; P < 0.001) by reai-time PCR test and by Western-blot analysis respectively. However, this inhibitory role can be effectively reversed by doxorubicin. The significant difference existed in the killing rate between the groups (P < 0.001) except between CTL+SK-N-SH group and CTL+SK-N-SH+DOX group (P > 0.05). There were significant differences in the levels of IL-2 (P < 0.001) and IFN-γ (P < 0.001) among the groups. Conclusions This study provided the novel method to enhance immunotherapeutic effects for neuroblastoma by using doxorubicin to targeted inhibition of MDSCs.