Recurrent hepatocellular carcinoma cells with stem cell-like properties: possible targets for immunotherapy.

Background Aims: Hepatocellular carcinoma (HCC) recurs with high frequency. Characterization of recurrent HCC cells will facilitate the design of future therapeutic strategies for recurrent HCC.

Methods: Two cell lines, Hep-11 and Hep-12, were established from the same HCC patient's primary and recurrent tumor tissues, respectively, and then analyzed for stem cell-like properties, immune evasion strategies and immunogenicity.

Results: Compared with Hep-11 cells, Hep-12 cells expressed higher levels of liver progenitor cell makers and displayed persistent tumorigenic potential in the serial transplantation assay. Although Hep-12 cells down-regulated human leukocyte antigen (HLA) class I expression, they could still be recognized and killed by autologous-activated tumor-infiltrating lymphocytes (TIL) in vitro. Pre-treatment with cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) increased the expression of HLA class I molecules on Hep-12 cells, and rendered them more susceptible to CD8(+) T-cell-mediated recognition and TIL-mediated cytotoxicity in vitro.

Conclusions: Our results indicate that Hep-12 cells possess stem cell-like properties, are susceptible to autologous-activated TIL-mediated recognition and cytotoxicity, and pre-treatment with TNF-alpha and IFN-gamma enhances their immunogenicity. This is the first evidence to support the hypothesis that immunotherapy can be used to target recurrent HCC cells with stem cell-like properties. This strategy may be an effective therapeutic approach to prevent HCC recurrence and control recurrent HCC growth.