Tumor regulation of the tissue environment in the liver

Abstract

The tumor microenvironment (TME) in the liver plays an important role in primary and metastatic liver tumor formation and tumor growth promotion. Cellular and non-cellular components of the TME significantly influence tumor development, growth, metastatic spread, anti-tumor immunity and response to tumor therapy. The cellular components of the TME in the liver not only consist of infiltrating immune cells, but also of liver-resident cells such as liver sinusoidal endothelial cells (LSEC) and hepatic stellate cells (HSC), which promote tumor growth by negatively regulating tumor-associated immune responses. In this review, we characterize cells of the TME with pro- and anti-tumor function in primary and metastatic liver tumors. Furthermore, we summarize mechanisms that permit growth of hepatic tumors despite the occurrence of spontaneous anti-tumor immune responses and how novel therapeutic approaches targeting the TME could unleash tumor-specific immune responses to improve survival of liver cancer patients.

Keywords: Hepatocellular carcinoma; Immunotherapy; Liver immunology; Liver metastases; Tumor immunology; Tumor microenvironment.

Fig. 1

Components of the tumor microenvironment restraining anti-tumor immune cells. Following activation, T cells and NK cells target tumors for tumor cell killing. However, liver resident cells and/or liver infiltrating immune cells such as immunosuppressive myeloid cells or regulatory T cells inhibit their anti-tumor function. Furthermore, the underlying liver disease also negatively regulates T cell and NK cell function either directly by inducing of CD4 T cell death or indirectly by recruiting imunosuppressive myeloid cells.

Fig. 2

Anti-tumor immune cells and mechanisms restraining their anti-tumor function. Molecular mechanisms inhibiting anti-tumor T cells (left) and anti-tumor NK cells (right) are shown. Therapeutic strategies to reverse this inhibition in order to unleash T cell and NK cell function are provided at the bottom of each box. Question marks indicate proposed, not yet studied approaches.

Fig. 3

Pro-tumor effector mechanisms of immune and non-immune cells in HCC. Molecular mechanisms of regulatory T cells (upper left), myeloid-derived suppressor cells (upper right), liver sinusoidal endothelial cells (lower left), tumor-associated macrophages (bottom center) and hepatic stellate cells (lower right) that support tumor growth are shown. Therapeutic strategies to counter these mechanisms are provided at the bottom of each box. Question marks indicate proposed, not yet studied approaches.