Activated tumor-infiltrating CD4+ regulatory T cells... : Hepatology (original) (raw)

Hepatobiliary Malignancies

Activated tumor-infiltrating CD4+ regulatory T cells restrain antitumor immunity in patients with primary or metastatic liver cancer

Pedroza-Gonzalez, Alexander1; Verhoef, Cornelis2; Ijzermans, Jan N. M.2; Peppelenbosch, Maikel P.1; Kwekkeboom, Jaap1; Verheij, Joanne3; Janssen, Harry L. A.1; Sprengers, Dave1,4,*

1Departments of Gastroenterology and HepatologyErasmus MC-University Medical Centre, Rotterdam, The Netherlands

2SurgeryErasmus MC-University Medical Centre, Rotterdam, The Netherlands

3Departments of Pathology, Erasmus MC-University Medical Centre, Rotterdam, The Netherlands

4Department of Gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands

*Department of Gastroenterology and Hepatology, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands

Email: [email protected]

Received 14 March 2012; Accepted 24 July 2012

Published online 4 December 2012.

2Potential conflict of interest: Nothing to report.

1Supported 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.

Abstract

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)

Abbreviations: CFSE, carboxyfluorescein diacetate succinimidyl ester; CMV, cytomegalovirus; CRC, colorectal cancer; CTLA-4, cytotoxic T lymphocyte-associated antigen 4; DC, dendritic cell; ELISA, enzyme-linked immunosorbent assay; GITR, glucocorticoid-induced tumor necrosis factor receptor; GITRL, GITR ligand; GM-CSF, granulocyte-macrophage colony-stimulating factor; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; ICOS, inducible T cell costimulator; LM-CRC, liver metastases from colorectal cancer; mDC, myeloid dendritic cell; MNC, mononuclear cell; NK, natural killer; NKT, natural killer T; NL, normal liver; TL, tumor lysate; Treg, regulatory T cell; PB, peripheral blood; PBMC, peripheral blood mononuclear cell; TFL, tumor-free liver; TIL, tumor-infiltrating lymphocyte; TNF-α, tumor necrosis factor-α.