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. Aims 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-γ 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-γ 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.