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. γδ 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 γδ T cells is essential for orchestrating effective immunotherapy strategies. In this study, we have investigated the immunophenotype and function of γδ T cells in hepatocellular carcinoma (HCC) patients. Methods The phenotype of γδ 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 γδ T cells was conducted directly after γδ T cell isolation. Results The infiltration of γδ T cells in tumoral tissues was significantly reduced compared to paired peritumoral tissues. Impairment in degranulation of the granule pathway and downregulation of IFN-γ secretion were also demonstrated in HCC-infiltrating γδ T cells, which was in agreement with the results of gene microarray analysis, and further strengthened by the compromised specific cytotoxicity and IFN-γ secretion in vitro . Moreover, isolated HCC-infiltrating CD4 + CD25 + regulatory T cells (Treg cells) directly suppressed the cytotoxic function and IFN-γ secretion of γδ T cells in a TGFβ- and IL-10-dependent manner. Conclusions The effector function of γδ 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.