Naturally occurring, tumor-specific CD8+ T cells in patients with hepatocellular carcinoma display a clear immunodominance

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and ranks third in mortality. This is partly due to a limited number of available therapeutic approaches. Since several studies found that the immune response directed against the tumor is associated with prognosis, immunotherapy is a potential future way of treatment. To develop such immune-based therapies, a better understanding of the natural immune response against HCC is obligatory. To address this issue, we used overlapping peptides covering the entire sequence of four prominent tumor-associated antigens (TAAs) in HCC, i.e. α-fetoprotein (AFP), Glypican–3, melanoma-associated gene-A1 (MAGE-A1) and NY-ESO–1. CD8⁺ T cells obtained from blood and tumor samples of a large cohort of HCC patients (n=96) as well as from the blood of controls (n=19) were stimulated with these peptides and analyzed for the production of interferon-γ. We found that TAA-specific immune responses were readily detectable in HCC patients at a significantly higher frequency than in controls (p=0.0017). We could identify a clear hierarchy between the individual antigens and several immunodominant regions within the respective TAAs. In addition, several responses were fine-mapped, leading to the identification of novel dominant tumor-specific epitopes. A further tetramer-analysis revealed that the tumor-specific CD8⁺ T cells could expand specifically in vitro but remained dysfunctional with respect to effector functions. In sum, our results indicate that HCC induces a broad immune response targeting several antigens and epitopes. However, the tumor-specific CD8⁺ T cells are clearly functionally impaired. These results indicate that insufficient immune-mediated control of HCC is not due to a lack of priming of CD8⁺ T cell responses but rather associated with impaired effector functions of these cells. These results have important implications for the further development of immune-based therapies for HCC.

CD8+ T cells - Hepatocellular carcinoma - tetramer - tumor immunity - tumor-associated antigen