Tim-3 expression and its role in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is one of the most common tumors in the world, and its mortality is still on the rise. Limited treatments and low chemotherapy sensitivity of HCC make new therapeutic strategies urgently needed. With the rise of immune checkpoint blockade, anti-CTLA-4 antibodies and anti-PD-1 antibodies have shown therapeutic effects in various tumors. T cell immunoglobulin mucin-3 (Tim-3), a newly discovered immune checkpoint molecule, plays a major role in the development of HCC. Tim-3 can be used to evaluate the prognosis and therapeutic effects in HCC, and Tim-3 intervention has shown anti-tumor effects in preclinical experiments. This review summarizes findings regarding Tim-3 and HCC in recent years and discusses the rationale of Tim-3 as a therapeutic target for HCC.

Keywords: Hepatocellular carcinoma; Immune checkpoint blockade; Immunotherapy; Tim-3.

Fig. 1

Pattern diagram of gene-edited CAR-T cells. CAR-T cells express CAR molecules against tumor-associated antigens (TAAs), which mediate specific localization and elimination of tumor cells by interacting with the TAA expressing on tumor cell surface. HCC cells are able to express ligands of immune checkpoints. The interaction of immune checkpoints and ligands leads to T cell exhaustion and apoptosis, which induces dysfunction and apoptosis of CAR-T cells as well. The immune checkpoint molecules on gene-edited CAR-T cells can be knocked out with CRISPR/cas9 system, which enables the gene-edited CAR-T cells to specifically recognize HCC cells, conduct anti-tumor responses, and avoid CAR-T cell exhaustion due to immune checkpoint pathways

Fig. 2

Regulation and functions of Tim-3 in HCC. Cytokines, such as IL-2, IL-7, IL-12, IL-17, TGF-β, and tumor-derived exosomes induce Tim-3 expression in T cells. Tim-3+ T cells present exhaustion phenotypes and reduced production of IFN-γ, IL-2, and TNF-α, indicating impaired anti-tumor immunity. Binding of Gal-9 to Tim-3+ effector T cells further mediates effector T cell apoptosis. Tim-3+ Tregs exert greater suppressor functions, producing reduced IFN-γ and IL-2 as well. Gal-9-expressing cells, including TAMs and DCs, are involved in the interaction of Gal-9 with Tim-3, further leading to Tim-3+ T cell exhaustion and apoptosis. HCC-derived TGF-β upregulates Tim-3 expression on TAMs and Tim-3 overexpression then facilitates M2 polarization of TAMs, further promoting HCC growth, migration, and invasion by the IL-6 pathway. Tim-3 on HCC cells promotes HCC proliferation, migration, and invasion in an IL-6 autocrine manner