Enhancement of DC vaccine efficacy via regulation of interleukin-6 receptor signaling (66.2)

Abstract

Abstract Tumor microenvironment has emerged as one of the major obstacles against the clinical efficacy of dendritic cell (DC) vaccines. Tumor-derived IL-6 inhibits DC maturation, leading to suppression of T cell-mediated immune response. Based on the findings showing that infusion of blocking anti-IL-6 mAb regressed tumor growth, we reasoned that knockdown of IL-6 receptor signaling could improve the capacity of DC vaccine in tumor-specific T cell activation. We injected mice with a cervical cancer line TC-1 that are expressing human papilloma virus-16 E7 oncogene and IL-6 in vivo, and immunized them with E7 peptide-pulsed bone-marrow-derived DC (BMDC) transfected with IL-6Rα siRNA (siIL-6Rα DC) or treated with IL-6 receptor signal competitor (IL-6RC DC). TC-1-bearing mice immunized with siIL-6Rα DC or IL-6RC showed an obvious decrease in tumor growth and prolonged survival compared to the control mice. siIL-6Rα DC and IL-6RC DC vaccines significantly enhanced the frequency of tumor-specific CD8+ CTLs- producing effector molecules such as IFN-γ, TNF-α, FasL, perforin, and granzyme B, and generated more CD8+ memory T cells. Our results suggest that DC vaccine with regulation of IL-6R signaling may potentiate the therapeutic efficacy of conventional DC vaccines.