Cisplatin induces tolerogenic dendritic cells in response to TLR agonists via the abundant production of IL-10, therby promoting Th2- and Tr1-biased T-cell immunity
Although many advantageous roles of cisplatin (cis-diamminedichloroplatinum
(II), CDDP) have been reported in cancer therapy, the immunomodulatory roles of
cisplatin in the phenotypic and functional alterations of dendritic cells (DCs) are
poorly understood. Here, we investigated the effect of cisplatin on the functionality
of DCs and the changes in signaling pathways activated upon toll-like receptor (TLR)
stimulation. Cisplatin-treated DCs down-regulated the expression of cell surface
molecules (CD80, CD86, MHC class I and II) and up-regulated endocytic capacity in
a dose-dependent manner. Upon stimulation with various TLR agonists, cisplatintreated
DCs showed markedly increased IL-10 production through activation of the
p38 MAPK and NF-κB signaling pathways without altering the levels of TNF-α and IL-
12p70, indicating the cisplatin-mediated induction of tolerogenic DCs. This effect was
dependent on the production of IL-10 from DCs, as neither DCs isolated from IL-10-
/- mice nor IL-10-neutralized DCs generated tolerogenic DCs. Interestingly, DCs that
were co-treated with cisplatin and lipopolysaccharide (LPS) exhibited a decreased
immunostimulatory capacity for inducing the proliferation of Th1- and Th17-type T
cells; instead, these DCs contributed to Th2-type T cell immunity. Furthermore, in
vitro and in vivo investigations revealed a unique T cell population, IL-10-producing
CD3+CD4+LAG-3+CD49b+CD25-Foxp3- Tr1 cells, that was significantly increased
without altering the Foxp3+ regulatory T cell population. Taken together, our results
suggest that cisplatin induces immune-suppressive tolerogenic DCs in TLR agonistinduced
inflammatory conditions via abundant IL-10 production, thereby skewing Th
cell differentiation towards Th2 and Tr1 cells. This relationship may provide cancer
cells with an opportunity to evade the immune system.1231sciescopu
