title: Suppression of Tregs by anti-glucocorticoid induced TNF receptor antibody enhances the antitumor immunity of interferon-α gene therapy for pancreatic cancer.
abstract: 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.
authors.affiliation: Division of Gene and Immune Medicine, National Cancer Center Research Institute, Tokyo, Japan; Department of Urology, St. Marianna University, Kanagawa, Japan.
authors.forename: Kouichirou
authors.initials: K
authors.lastname: Aida
authors.forename: Reina
authors.initials: R
authors.lastname: Miyakawa
authors.forename: Koji
authors.initials: K
authors.lastname: Suzuki
authors.forename: Kenta
authors.initials: K
authors.lastname: Narumi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Udagawa
authors.forename: Yuki
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Chikaraishi
authors.forename: Teruhiko
authors.initials: T
authors.lastname: Yoshida
authors.forename: Kazunori
authors.initials: K
authors.lastname: Aoki
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D051858:Forkhead Transcription Factors / Q000276:immunology; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology*; D007167:Immunotherapy / Q000379:methods; D015552:Injections, Intralesional; D016898:Interferon-alpha / Q000008:administration & dosage / Q000235:genetics* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000276:immunology* / Q000628:therapy*; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*; D059016:Tumor Microenvironment / Q000187:drug effects / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D016898:Interferon-alpha; D018124:Receptors, Tumor Necrosis Factor
keywords: Anti-glucocorticoid induced TNF receptor antibody; interferon-α gene therapy; pancreatic cancer