We have reported that
interferon (IFN)-α can attack
cancer cells by multiple antitumor mechanisms including the induction of direct
cancer cell death and the enhancement of an immune response in several
pancreatic cancer models. However, an immunotolerant microenvironment in the
tumors is often responsible for the failure of the
cancer immunotherapy. Here we examined whether the suppression of regulatory T cells (Tregs) within
tumors can enhance an antitumor immunity induced by an intratumoral IFN-α gene transfer. First we showed that an intraperitoneal administration of an agonistic anti-
glucocorticoid induced
TNF receptor (GITR)
monoclonal antibody (mAb), which is reported to suppress the function of Tregs, significantly inhibited subcutaneous
tumor growth in a murine
pancreatic cancer model. The anti-GITR mAb was then combined with the intratumoral injection of the IFN-α-adenovirus vector. The treatment with the antibody synergistically augmented the antitumor effect of IFN-α gene therapy not only in the vector-injected
tumors but also in the vector-uninjected
tumors. Immunostaining showed that the anti-GITR mAb decreased Foxp3(+) cells infiltrating in the
tumors, while the intratumoral IFN-α gene transfer increased CD4(+) and CD8(+) T cells in the
tumors. Therefore, the combination
therapy strongly inclined the immune balance of the tumor microenvironment in an antitumor direction, leading to a marked systemic antitumor effect. The CCR5 expression on Tregs was downregulated in the antibody-treated mice, which may explain the decrease of
tumor-infiltrating Tregs. The combination of Treg-suppression by GITR mAb and the
tumor immunity induction by IFN-α gene therapy could be a promising therapeutic strategy for
pancreatic cancer.