Glycogen Synthase Kinase-3? (GSK-3?) Inhibition Enhances Dendritic Cell-based Cancer Vaccine Potency via Suppression of Interferon-?-induced Indoleamine 2,3-Dioxygenase Expression.

ABSTRACT: Indoleamine 2,3-dioxygenase (IDO) functions as a crucial mediator of tumor-mediated immune tolerance by causing T-cell suppression via tryptophan starvation in a tumor environment. Glycogen synthase kinase-3? (GSK-3?) is also involved in immune and anti-tumor responses. However, the relativity of these proteins has not been as well defined. Here, we found that GSK-3?-dependent IDO expression in the dendritic cell (DC) plays a role in anti-tumor activity via the regulation of CD8(+) T-cell polarization and cytotoxic T lymphocyte activity. By the inhibition of GSK-3?, attenuated IDO expression and impaired JAK1/2-Stat signaling crucial for IDO expression were observed. Protein kinase C? (PKC?) activity and the interaction between JAK1/2 and Stat3, which are important for IDO expression, were also reduced by GSK-3? inhibition. CD8(+) T-cell proliferation mediated by OVA-pulsed DC was blocked by interferon (IFN)-?-induced IDO expression via GSK-3? activity. Specific cytotoxic T lymphocyte activity mediated by OVA-pulsed DC against OVA-expressing EG7 thymoma cells but not OVA-nonexpressing EL4 thymoma cells was also attenuated by the expressed IDO via IFN-?-induced activation of GSK-3?. Furthermore, tumor growth that was suppressed with OVA-pulsed DC vaccination was restored by IDO-expressing DC via IFN-?-induced activation of GSK-3? in an OVA-expressing murine EG7 thymoma model. Taken together, DC-based immune response mediated by interferon-?-induced IDO expression via GSK-3? activity not only regulates CD8(+) T-cell proliferation and cytotoxic T lymphocyte activity but also modulates OVA-pulsed DC vaccination against EG7 thymoma.

SUBMITTER: Noh KT 

PROVIDER: S-EPMC4424368 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature