Is the liver an important site for the development of immune tolerance to tumours?

Despite the enormous interest in the field of tumour immunology, and the development of vaccine based strategies for immunotherapy of tumours, results in patients with cancer have been disappointing. This is partly due to the lack of development of clearly defined anti-tumour immune responses. The basis for the induction of specific anti-tumour non-responsiveness is not known. Recently, the liver has been recognised as an important organ in the regulation of peripheral immunological responses. It is characterised by a remarkable ability to induce tolerance to antigens from a variety of sources. Oral tolerance to food antigens, antigens from gut flora and other antigens administered via the oral route is partly dependent upon local immunoregulation in the liver. Transplantation of liver tissue shows a remarkable ability to induce tolerance in some species, not only to liver tissue but also to other organs and tissues transplanted at the same time. This tolerance can be transferred by adoptive transfer of lymphocytes. It has been suggested that the establishment of persistent infection in the liver by hepatitis viruses, may partly depend on the tolerogenic environment of the liver, and that this may also play a role in the development of hepatocellular carcinoma in patients with chronic infections with these viruses. The liver is also a common and an important site for the development of metastases from many primary tumours. This is partly dependent upon the anatomic location and structure of the liver, but may also partly reflect the exploitation of the tolerogenic environment in the liver, allowing micrometastases to colonise and grow. This may account for the fact that the liver is such a common site for metastasis. Furthermore, once tolerance to tumour antigens is established in the liver, tolerated lymphocytes may migrate from the liver back to primary tumours and exacerbate immunological non-responsiveness at tumour sites. Indeed, if this happens early in tumour development, liver dependent tolerance to tumour antigens may play a significant role in tumour progression, and may partly determine impaired tumour responses in vaccine based immunotherapy strategies.