Adoptive T-cell therapy to treat liver cancer: Is the liver microenvironment key?

Abstract

Hepatocellular carcinoma (HCC) reflects the 5th most common cause for cancer related deaths worldwide with approximately 800.000 deceases per year and is the third most frequent cause for death worldwide [1]. In African or Asian countries HCC has become the most common cause for cancer-related death, mainly as a consequence of viral infections with Hepatitis B and C-viruses (HBV; HCV). Notably, in Europe and the USA HCC is on the rise, reflecting the fastest increasing cancer type in recent years in the USA. Prospectively this trend will worsen in the USA and Europe since e.g. HCV had already superseded HIV as a cause of death. Moreover, in industrialized countries not only HBV- or HCV-infections surmount this development but more and more high fat diet induced non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver disease (NAFLD) lead to liver cancer [1]. Given the effort that has been invested in the past year to understand and treat HCC - either induced by viruses, high fat diet or chronic alcohol consumption - clinical success has been relatively small. Up to now the most effective intervention to prolong life-span of HCC patients has been liver transplantation for those with a single, small nodule – which is the exception. Chemo- and radiotherapy do not lead to an amelioration of the patient's status but rather to tumor cell resistance in patients with HCC. Moreover, the aberrant liver function of HCC patients rather reduces the efficacy of the chemotherapy than promoting it. Various novel drugs have been investigated, and the pantyrosine kinase inhibitor Sorafenib [1] has become the standard of care for HCC therapy. Except transplantation, these regimens, however, are rather palliative than curative [1]. Thus, apart from the demand to broaden HCC surveillance programs to reduce overall disease specific mortality for people at risk, an efficient therapy to treat HCC is urgently needed. In contrast to the antigenic heterogeneity of high fat diet or alcohol induced HCC, that express tumor-associated (self) antigens or individually mutated antigens, tumor cells of virus-induced HCC equally express - and may be addicted to - viral proteins, that are recognized by the immune system. Nevertheless, virus-induced HCC often escapes immune-surveillance. In a related virus-induced HCC mouse model we have shown that tumor-specific T cells are functionally activated by the virus infection but that the developing HCC escapes destruction since T cells can only poorly infiltrate HCC and the few remaining, infiltrating T cells are rendered dysfunctional in the liver [2]. Therefore, immunotherapy for treating virus-induced HCC, in particular adoptively transferred T-cells targeted against viral oncogenes acting as shared tumor-specific antigens, could represent a very promising and successful approach.