Potential conflict of interest: Nothing to report.
Article first published online: 4 DEC 2012
Copyright © 2012 American Association for the Study of Liver Diseases
Volume 57, Issue 1, pages 183–194, January 2013
How to Cite
Pedroza-Gonzalez, A., Verhoef, C., Ijzermans, J. N. M., Peppelenbosch, M. P., Kwekkeboom, J., Verheij, J., Janssen, H. L. A. and Sprengers, D. (2013), Activated tumor-infiltrating CD4+ regulatory T cells restrain antitumor immunity in patients with primary or metastatic liver cancer. Hepatology, 57: 183–194. doi: 10.1002/hep.26013
Supported by the Erasmus MC University Medical Center (fellowship award to D. S.). D. S. was a clinical research trainee of the Netherlands Organisation of Scientific Research. Erasmus Trustfonds financial support was granted to A. P.-G.
- Issue published online: 7 JAN 2013
- Article first published online: 4 DEC 2012
- Accepted manuscript online: 22 AUG 2012 03:20AM EST
- Manuscript Accepted: 24 JUL 2012
- Manuscript Received: 14 MAR 2012
The mechanisms that enable liver cancer to escape elimination by the immune system remain unclear, but their elucidation may provide novel therapeutic interventions. We investigated the influence of tumor-infiltrating regulatory T cells on tumor-specific T cell responses in patients with liver cancer, using ex vivo isolated cells from individuals with hepatocellular carcinoma (HCC) or liver metastases from colorectal cancer (LM-CRC). Here we report that in both HCC and LM-CRC, CD4+CD25+Foxp3+ regulatory T cells (Tregs) accumulate in the tumor milieu and are potent suppressors of autologous tumor-specific T cell responses. Especially in LM-CRC, where Treg accumulation is more prominent, there is good evidence for local proliferation of Tregs at the cancer site. We show that tumor Tregs up-regulate the expression of glucocorticoid-induced tumor necrosis factor receptor (GITR) compared with Tregs in tumor-free liver tissue and blood. Importantly, treatment with soluble GITR ligand (GITRL) induces a decrease in the suppression mediated by the activated tumor-infiltrating Tregs and restores the proliferative capacity and cytokine production of CD4+CD25− T cells. Conclusion: Our results show that tumor-associated Tregs are critical for immune evasion in liver cancer, and we propose that GITRL constitutes a rational treatment for this disease. (HEPATOLOGY 2013)