TGF-β1 contributes to CD8(+) Treg induction through p38 MAPK signaling in ovarian cancer microenvironment

CD8(+) regulatory T cells (Tregs) contribute to cancer progression and immune evasion. We previously reported that CD8(+) Tregs could be induced in vitro by co-culture of CD8(+) T cells with the OC cell lines SKOV3/A2780. Here, we described the role of TGF-β1 in CD8(+) Treg induction by the OC microenvironment. OC patients expressed high levels of TGF-β1, as did the co-culture supernatant from CD8(+) T cells and SKOV3. Additionally, TGF-β1 levels were positively correlated with CD8(+) Treg percentages in OC. Neutralization experiments, cytokine studies and proliferation assays revealed that the in vitro-induced CD8(+)Tregs depended at least partially on up-regulated expression of TGF-β1 to exert their suppressive function. CD8(+) T cells cultured with SKOV3 exhibited marked activation of p38 MAPK than CD8(+) T cells cultured alone, which could be inhibited by TGF-β1-neutralizing antibody. Moreover, the p38 specific inhibitor SB203580 dose-dependently blocked the TGF-β1 activated conversion of CD8(+) T cells into CD8(+) Tregs. These data suggested that in vitro-induction of CD8(+) Tregs depended in part on TGF-β1 activation of p38 MAPK signaling. Therefore, p38 MAPK could be a therapeutic target in OC anti-tumor immunotherapy.