New insights into T-cell exhaustion in liver cancer: from mechanism to therapy

Abstract

Liver cancer is one of the most common malignancies. T-cell exhaustion is associated with immunosuppression of tumor and chronic infection. Although immunotherapies that enhance the immune response by targeting programmed cell death-1(PD-1)/programmed cell death ligand 1 (PD-L1) have been applied to malignancies, these treatments have shown limited response rates. This suggested that additional inhibitory receptors (IRs) also contributed to T-cell exhaustion and tumor prognosis. Exhausted T-cells (Tex) in the tumor immune microenvironment (TME) are usually in a dysfunctional state of exhaustion, such as impaired activity and proliferative ability, increased apoptosis rate, and reduced production of effector cytokines. Tex cells participate in the negative regulation of tumor immunity mainly through IRs on the cell surface, changes in cytokines and immunomodulatory cell types, causing tumor immune escape. However, T-cell exhaustion is not irreversible and targeted immune checkpoint inhibitors (ICIs) can effectively reverse the exhaustion of T-cells and restore the anti-tumor immune response. Therefore, the research on the mechanism of T-cell exhaustion in liver cancer, aimed at maintaining or restoring the effector function of Tex cells, might provide a new method for the treatment of liver cancer. In this review, we summarized the basic characteristics of Tex cells (such as IRs and cytokines), discussed the mechanisms associated with T-cell exhaustion, and specifically discussed how these exhaustion characteristics were acquired and shaped by key factors within TME. Then new insights into the molecular mechanism of T-cell exhaustion suggested a potential way to improve the efficacy of cancer immunotherapy, namely to restore the effector function of Tex cells. In addition, we also reviewed the research progress of T-cell exhaustion in recent years and provided suggestions for further research.

Keywords: Immune checkpoint inhibitors; Liver cancer; T-cell; T-cell exhaustion.

Fig. 1

The development and characteristic of T-cell exhaustion. During acute infection, naive T cells are activated by antigen and rapidly proliferate reactive T-cells. When antigen or inflammatory-induced acute infection subsided, effector T-cells further differentiated into memory T-cells, retaining the ability to reactivate effector function quickly and efficiently in secondary infections. In contrast, in chronic infections and cancers, the antigen remains exist. In chronic infections and cancer, with the persistent chronic stimulation of antigen, T-cells gradually lose their effector function, which is called T-cell exhaustion. As T-cell exhaustion progresses, the ability of immune checkpoint inhibitors to reverse failure becomes less effective. T-cell exhaustion is characterized by impaired cytotoxicity, reduced production of cytokines such as IL-2, TNF-α, and IFN-γ, and overexpression of multiple inhibitory receptors such as PD-1, CTLA-4, TIGIT, TIM-3 and LAG-3

Fig. 2

T-cells promoted the expression of PD-L1 in cancer cells. T-cells, especially CD8 T-cells, secrete IFN-γ after recognizing tumor antigen, then bind to corresponding receptors and promoted the expression of PD-L1 through JAK2-STAT1 pathway or PI3K/Akt pathway

Fig. 3

Macrophage polarization. Macrophages polarize into M1 or M2 macrophages. M1-polarized macrophages are activated by Th1 cytokines such as IFN-γ and TNF-α. M1 polarization produces pro-inflammatory substances such as IL-12 or TNF-α. M2-polarized macrophages are activated by Th2 cytokines IL-13 and IL-4, have anti-inflammatory effects, and produce TGF-β and IL-10

Fig. 4

Potential mechanisms of T-cell exhaustion. The development of T-cell exhaustion may be attributed to complex tumor immune microenvironments such as continued stimulation of tumor antigens, immunosuppressive cells, including MDSCs, Tregs, and TAMs, the increase of inhibitory receptors on the surface of T-cells, and transcriptomics and epigenetic changes, and metabolic reprogramming

Fig. 5

Strategies to reverse T-cell exhaustion. Inhibitory receptor blockade. Adding CARs methods. Targeting immune suppressor cells. Blocking cytokine. Targeting VEGF/VEGFR. Chemotherapy or radiotherapy