title: SOCS1 silencing can break high-dose dendritic cell immunotherapy-induced immune tolerance.
abstract: Dendritic cells (DCs) play a pivotal role in T cell-mediated immunity and have been shown to induce strong anti-tumor immune responses. As of yet, only a limited number of objective tumor regressions have been observed in clinical studies using a DC vaccine. Suppressor of cytokine signaling-1 (SOCS1) is a key negative regulator of the JAK/STAT signal pathway and plays an essential role in suppressing systemic autoimmunity that is mediated by DCs. The aim of this study was to investigate whether SOCS1-silenced DCs can break the vaccine-induced immune tolerance stimulated by high-dose DC, thereby enhancing anti-tumor activity. In the mouse melanoma model, we found that a 2x106 TRP2-pulsed DC vaccine was able to induce immune tolerance, while a 2x106 SOCS1-silenced DC/TRP2 vaccine prevented immune tolerance. Further experiments revealed that activation-induced T cell death (AICD) through the Fas/Fas-L pathway may play a crucial role in immune tolerance induced by 2x106 TRP2-pulsed DC. SOCS1-silencing in DCs could prevent immune tolerance by inhibiting Fas and Fas-L expression, induced by an increase in IL-12p70 and IL-6 production. In addition, in 2x106 SOCS1-silenced DC/TRP2 immunized mice, higher levels of IL-12p70 and IFN-γ and lower IL-17 production may inhibit tumor angiogenesis and therefore assist in breaking immune tolerance. In conclusion, high-doses of DCs can inhibit the vaccine-induced AICD of T cells and cytokine regulation in tumor angiogenesis. These results indicate that SOCS1-silenced DC vaccines may greatly enhance anti-tumor activity by breaking self-tolerance.
authors.affiliation: Shanghai Jiao Tong University Medical School, Shanghai Institute of Immunology, Shanghai 200025, P.R. China.
authors.forename: Qinghai
authors.initials: Q
authors.lastname: Hu
authors.forename: Xia
authors.initials: X
authors.lastname: Qin
authors.forename: Gaochao
authors.initials: G
authors.lastname: Qian
authors.forename: Shan
authors.initials: S
authors.lastname: Jiang
authors.forename: Haiyan
authors.initials: H
authors.lastname: Li
authors.forename: Min
authors.initials: M
authors.lastname: Jiang
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Li
authors.forename: Si-Yi
authors.initials: SY
authors.lastname: Chen
authors.forename: Ying Qin
authors.initials: YQ
authors.lastname: Zang