The functional impairment of HCC-infiltrating γδ T cells, partially mediated by regulatory T cells in a TGFβ- and IL-10-dependent manner

Background & Aims: The immunosuppressive network within the tumor microenvironment is one of the major obstacles to the success of cancer immunotherapy. gamma delta T cells are attractive effectors for cancer immunotherapy. Nevertheless, the promising anti-tumor effect in vitro is partially if not totally mitigated in vivo. Thus, understanding the immune status of tumor-infiltrating gamma delta T cells is essential for orchestrating effective immunotherapy strategies. In this study, we have investigated the immunophenotype and function of gamma delta T cells in hepatocellular carcinoma (HCC) patients. Methods: The phenotype of gamma delta T cells in peripheral blood, and peritumoral and tumoral tissues of HCC patients (n = 61) was characterized by flow cytometry. Functional analysis of the HCC-infiltrating gamma delta T cells was conducted directly after gamma delta T cell isolation. Results: The infiltration of gamma delta T cells in tumoral tissues was significantly reduced compared to paired peritumoral tissues. Impairment in degranulation of the granule pathway and downregulation of IFN-gamma secretion were also demonstrated in HCC-infiltrating gamma delta T cells, which was in agreement with the results of gene microarray analysis, and further strengthened by the compromised specific cytotoxicity and IFN-gamma secretion in vitro. Moreover, isolated HCC-infiltrating CD4(+)CD25(+) regulatory T cells (Treg cells) directly suppressed the cytotoxic function and IFN-gamma secretion of gamma delta T cells in a TGF beta- and IL-10-dependent manner. Conclusions: The effector function of gamma delta T cells was substantially impaired in HCC, which is partially mediated by Treg cells. We propose a new mechanism by which immune privilege develops within the tumor milieu. (c) 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.