Suppression of Tregs by anti-glucocorticoid induced TNF receptor antibody enhances the antitumor immunity of interferon-α gene therapy for pancreatic cancer.
Bottom Line: 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 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.
Affiliation: Division of Gene and Immune Medicine, National Cancer Center Research Institute, Tokyo, Japan; Department of Urology, St. Marianna University, Kanagawa, Japan.Show MeSH
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Mentions: It is known that a large number of tumor-infiltrating lymphocytes (TILs) result in a better antitumor effect for cancer patients.(25) To examine whether an increase of TILs in treated tumors is related to tumor growth suppression, immunohistochemical staining of CD4- and CD8-positive cells was performed in the Pan02 tumors 13 days after the injection of Ad-mIFN. The intratumoral IFN-α expression significantly increased the infiltration of CD4+ and CD8+ T cells in both vector-injected and vector-uninjected tumors, and the anti-GITR mAb also increased the number of CD4+ cells in the both tumors (Fig. 5a,b). Furthermore, the combination therapy of anti-GITR mAb and IFN-α gene transfer further increased the infiltration of CD4+ and CD8+ cells compared with the Ad-mIFN or anti-GITR mAb alone groups (Fig. 5a,b). Next, the infiltration of Foxp3+ cells was assessed in the treated Pan02 tumors. Interferon-α gene transfer and anti-GITR mAb administration decreased the number of Foxp3+ cells in the tumors, and the combination therapy markedly decreased Foxp3+ cells (Fig. 5c). Since a high effector T cells/Tregs ratio is associated with a favorable prognosis for cancer patients,(26) we calculated the ratio of CD4+ or CD8+ cells per Foxp3+ cells in the tumors. The ratios were markedly high in the combination therapy-treated tumors (Fig. 5d).
Affiliation: Division of Gene and Immune Medicine, National Cancer Center Research Institute, Tokyo, Japan; Department of Urology, St. Marianna University, Kanagawa, Japan.