Impact of immune tolerance mechanisms on the efficacy of immunotherapy in primary and secondary liver cancers

Abstract

The liver is a functionally unique organ with an immunosuppressive microenvironment. The liver is the sixth most common site of primary cancer in humans and is a frequent site of metastasis from other solid tumors. The development of effective therapies for primary and metastatic liver cancer has been challenging due to the complex metabolic and immune microenvironment of the liver. The liver tumor microenvironment (TME) in primary and secondary (metastatic) liver cancers is heterogenous and consists of unique immune and stromal cell populations. Crosstalk between these cell populations and tumor cells creates an immunosuppressive microenvironment within the liver which potentiates cancer progression. Immune checkpoint inhibitors (ICIs) are now clinically approved for the management of primary and secondary liver cancer and can partially overcome liver immune tolerance, but their efficacy is limited. In this review, we describe the liver microenvironment and the use of immunotherapy in primary and secondary liver cancer. We discuss emerging combination strategies utilizing locoregional and systemic therapy approaches which may enhance efficacy of immunotherapy in primary and secondary liver cancer. A deeper understanding of the immunosuppressive microenvironment of the liver will inform novel therapies and therapeutic combinations in order to improve outcomes of patients with primary and secondary liver cancer.

Keywords: Hepatocellular carcinoma (HCC); immunotherapy in liver cancer; liver metastases; tumor immune microenvironment.

Figure 1

Immunosuppressive mechanisms in the liver immune microenvironment. The tolerogenic liver environment supports the infiltration of regulatory immune cells that limit effector CD8⁺ T cell function, resulting in the suppression of anti-tumor immunity and the formation of a cancer-permissive pre-metastatic niche. Neutrophils recruit TAMs and Tregs, which directly inhibit CD8⁺ T cells. IL-10 and TGFβ promote Treg development and directly suppress CD8⁺ T cell function. MDSCs and ILCs also modulate CD8⁺ T cell function, while signaling by HSCs and LSECs induced by bacterial metabolites inhibits NK- and NKT-mediated immunity. Macrophages contribute to metastatic colonization in the liver through multiple mechanisms. Other cells in the liver also promote the seeding of metastatic cancer, including neutrophils, Tregs, HSCs, and LSECs. LTA, lipoteichoic acid; HSC, hepatic stellate cell; LSEC, liver sinusoidal endothelial cell; PE2, prostaglandin E2; NK, natural killer cell; NKT, natural killer T cell; MDSC, myeloid-derived suppressor cell; ILC, innate lymphoid cell; PD-L1, programmed death-ligand 1; PD-1, programmed cell death protein 1; TAMs, tumor-associated macrophages; LCFA, Long-chain fatty acid; DC, dendritic cell; GDF15, growth differentiation factor 15; NETs, neutrophil extracellular traps.