Targeted eliminating myeloid-derived suppressor cells with doxorubicin
by regulating STAT pathway to alleviate tumor immunosuppression in
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.