Suppression of Tregs by anti-glucocorticoid induced TNF receptor antibody enhances the antitumor immunity of interferon-α gene therapy for pancreatic cancer
Article first published online: 4 JAN 2014
© 2013 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Volume 105, Issue 2, pages 159–167, February 2014
How to Cite
Cancer Sci 105 (2014) 159–167
- Issue published online: 10 FEB 2014
- Article first published online: 4 JAN 2014
- Accepted manuscript online: 30 NOV 2013 02:05PM EST
- Manuscript Accepted: 27 NOV 2013
- Manuscript Revised: 25 NOV 2013
- Manuscript Received: 8 AUG 2013
- Ministry of Health
- Labour and Welfare of Japan
- National Institute of Biomedical Innovation
- National Cancer Center Research and Development Fund. Grant Number: 23-A-38
- Anti-glucocorticoid induced TNF receptor antibody;
- interferon-α gene therapy;
- pancreatic cancer
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.