title: The functional impairment of HCC-infiltrating γδ T cells, partially mediated by regulatory T cells in a TGFβ- and IL-10-dependent manner.
abstract: OBJECTIVE
  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.
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory for Carcinogenesis & Cancer Invasion, The Chinese Ministry of Education, Shanghai, People's Republic of China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Yi
authors.forename: Hong-Wei
authors.initials: HW
authors.lastname: He
authors.forename: Jia-Xing
authors.initials: JX
authors.lastname: Wang
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Cai
authors.forename: Yi-Wei
authors.initials: YW
authors.lastname: Li
authors.forename: Jian
authors.initials: J
authors.lastname: Zhou
authors.forename: Yun-Feng
authors.initials: YF
authors.lastname: Cheng
authors.forename: Jian-Jun
authors.initials: JJ
authors.lastname: Jin
authors.forename: Jia
authors.initials: J
authors.lastname: Fan
authors.forename: Shuang-Jian
authors.initials: SJ
authors.lastname: Qiu
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000473:pathology / Q000503:physiopathology*; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D016130:Immunophenotyping; D007167:Immunotherapy; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000502:physiology; D016753:Interleukin-10 / Q000502:physiology*; D008113:Liver Neoplasms / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000502:physiology*; D013601:T-Lymphocytes / Q000473:pathology / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000473:pathology / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000502:physiology*
chemical_list: D016692:Receptors, Antigen, T-Cell, gamma-delta; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D007371:Interferon-gamma