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Hepatocellular Carcinoma Immunopathogenesis: Clinical Evidence for Global T Cell Defects and an Immunomodulatory Role for Soluble CD25 (sCD25)

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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.

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Authors and Affiliations

  1. Section of Hepatobiliary Diseases, Department of Medicine, University of Florida, 1600 SW Archer Rd., PO Box 100214, Gainesville, FL, 32610-0214, USA

    Roniel Cabrera, Miguel Ararat, Mengde Cao, Yiling Xu & David R. Nelson

  2. Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL, 32610-0214, USA

    Clive Wasserfall, Mark A. Atkinson & Chen Liu

Authors
  1. Roniel Cabrera
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  2. Miguel Ararat
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  3. Mengde Cao
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  4. Yiling Xu
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  5. Clive Wasserfall
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  6. Mark A. Atkinson
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  7. Chen Liu
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  8. David R. Nelson
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Correspondence to Roniel Cabrera.

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Cabrera, R., Ararat, M., Cao, M. et al. Hepatocellular Carcinoma Immunopathogenesis: Clinical Evidence for Global T Cell Defects and an Immunomodulatory Role for Soluble CD25 (sCD25). Dig Dis Sci 55, 484–495 (2010). https://doi.org/10.1007/s10620-009-0955-5

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  • DOI: https://doi.org/10.1007/s10620-009-0955-5

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