Hepatocellular carcinoma immunopathogenesis: clinical evidence for global T cell defects and an immunomodulatory role for soluble CD25 (sCD25).
Roniel Cabrera, Miguel Ararat, Mengde Cao, Yiling Xu, Clive Wasserfall, Mark A Atkinson, Chen Liu, David R Nelson
Author Information
Roniel Cabrera: 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
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-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.
References
N Engl J Med. 2008 Jul 24;359(4):378-90
[PMID: 18650514]
