title: Hepatocellular carcinoma immunopathogenesis: clinical evidence for global T cell defects and an immunomodulatory role for soluble CD25 (sCD25).
abstract: BACKGROUND
  The mechanisms involved in hepatocellular carcinoma (HCC) establishing an immunologically tolerogenic tumor environment remain poorly characterized.
  
  
  OBJECTIVE
  This study evaluates effector T cell responses and soluble IL-2 receptor alpha chains (sCD25) in relation to HCC stage/survival and characterizes the impact of sCD25 on effectors.
  
  
  METHODS
  Effector cell responses with serum from HCC patients and in serum free conditions were assessed by IFN-gamma ELISpot, proliferation and ATP production assays at baseline, after depletion of sCD25, and after supplementation with recombinant sCD25. Sera sCD25 were measured by ELISA and any relationship with stage/survival was determined.
  
  
  RESULTS
  Hepatocellular carcinoma patients had marked global impairment in T cell responses at baseline which correlate with tumor burden and poor outcome. The impairment in immune responses is characterized by low IFN-gamma production, cell proliferation, and ATP production. Effector responses are impaired by serum from HCC patients in a dose-dependent manner, implicating soluble factors in the observed immunosuppression. Significant elevations in serum levels of sCD25 are found in patients with HCC, which correlate with tumor burden and a worse survival. T cell reactivity is inversely proportional to serum level of sCD25. Impaired T cell responses improve with sCD25 depletion from HCC serum or IL-2 supplementation suggesting impairment in IL-2 signaling. In contrast, adding increasing doses of sCD25 suppresses effector T cells, which partly involves induction of apoptosis.
  
  
  CONCLUSIONS
  These findings show that HCC patients have blunted T cell immunity that is partly related to elevated levels of sCD25, supporting a novel immuno-inhibitory role for this soluble receptor.
authors.affiliation: Section of Hepatobiliary Diseases, Department of Medicine, University of Florida, 1600 SW Archer Rd, PO Box 100214, Gainesville, FL 32610-0214, USA. cabrer@medicine.ufl.edu
authors.forename: Roniel
authors.initials: R
authors.lastname: Cabrera
authors.forename: Miguel
authors.initials: M
authors.lastname: Ararat
authors.forename: Mengde
authors.initials: M
authors.lastname: Cao
authors.forename: Yiling
authors.initials: Y
authors.lastname: Xu
authors.forename: Clive
authors.initials: C
authors.lastname: Wasserfall
authors.forename: Mark A
authors.initials: MA
authors.lastname: Atkinson
authors.forename: Chen
authors.initials: C
authors.lastname: Liu
authors.forename: David R
authors.initials: DR
authors.lastname: Nelson
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000097:blood / Q000276:immunology; D006528:Carcinoma, Hepatocellular / Q000097:blood / Q000276:immunology* / Q000473:pathology; D049109:Cell Proliferation; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007111:Immunity, Cellular; D053645:Interleukin-2 Receptor alpha Subunit / Q000097:blood / Q000276:immunology*; D008113:Liver Neoplasms / Q000097:blood / Q000276:immunology* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D013601:T-Lymphocytes / Q000276:immunology*; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; C508017:IL2RA protein, human; D053645:Interleukin-2 Receptor alpha Subunit