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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 ( T regs) 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  T regs, 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  T regs 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.

cancer science

Suppression of  T regs by anti‐glucocorticoid induced  TNF  receptor antibody enhances the antitumor immunity of interferon‐α gene therapy for pancreatic cancer