Suppressor of cytokine signaling 1 inhibits the maturation of dendritic cells involving the nuclear factor kappa B signaling pathway in the glioma microenvironment

摘要

Recurrence and diffuse infiltration challenge traditional therapeutic strategies for malignant glioma. Immunotherapy appears to be a promising approach to obtain long-term survival. Dendritic cells (DCs), the most specialized and potent antigen-presenting cells (APCs), play an important part in initiating and amplifying both the innate and adaptive immune responses against cancer cells. However, cancer cells can escape from immune surveillance by inhibiting maturation of DCs. Until the present, molecular mechanisms of maturation inhibition of DCs in the tumor microenvironment (TME) have not been fully revealed. Our study showed that pretreatment with tumor-conditioned medium (TCM) collected from supernatant of primary glioma cells significantly suppressed the maturation of DCs. TCM pretreatment significantly changed the morphology of DCs, TCM decreased the expression levels of CD80, CD83, CD86 and interleukin (IL)-12p70, while it increased the expression levels of IL-10, transforming growth factor (TGF)-beta and IL-6. RNA-Seq showed that TCM pretreatment significantly increased the gene expression level of suppressor of cytokine signaling 1 (SOCS1) in DCs. suppressor of cytokine signaling 1 (SOCS1) knock-down significantly antagonized the maturation inhibition of DCs by TCM, which was demonstrated by the restoration of maturation markers. TCM pretreatment also significantly suppressed T cell viability and T helper type 1 (Th1) response, and SOCS1 knock-down significantly antagonized this suppressive effect. Further, TCM pretreatment significantly suppressed p65 nuclear translocation and transcriptional activity in DCs, and SOCS1 knock-down significantly attenuated this suppressive effect. In conclusion, our research demonstrates that TCM up-regulate SOCS1 to suppress the maturation of DCs via the nuclear factor-kappa signaling pathway.