Natural Killer Cells and T Cells in Hepatocellular Carcinoma and Viral Hepatitis: Current Status and Perspectives for Future Immunotherapeutic Approaches

Abstract

Natural killer (NK) cells account for 25-50% of the total number of hepatic lymphocytes, which implicates that NK cells play an important role in liver immunity. The frequencies of both circulating and tumor infiltrating NK cells are positively correlated with survival benefit in hepatocellular cancer (HCC) and have prognostic implications, which suggests that functional impairment in NK cells and HCC progression are strongly associated. In HCC, T cell exhaustion is accompanied by the interaction between immune checkpoint ligands and their receptors on tumor cells and antigen presenting cells (APC). Immune checkpoint inhibitors (ICIs) have been shown to interfere with this interaction and have altered the therapeutic landscape of multiple cancer types including HCC. Immunotherapy with check-point inhibitors, aimed at rescuing T-cells from exhaustion, has been applied as first-line therapy for HCC. NK cells are the first line effectors in viral hepatitis and play an important role by directly eliminating virus infected cells or by activating antigen specific T cells through IFN-γ production. Furthermore, chimeric antigen receptor (CAR)-engineered NK cells and T cells offer unique opportunities to create CAR-NK with multiple specificities learning from the experience gained with CAR-T cells with potentially less adverse effects. This review focus on the abnormalities of NK cells, T cells, and their functional impairment in patients with chronic viral hepatitis, which contributes to progression to hepatic malignancy. Furthermore, we discuss and summarize recent advances in the NK cell and T cell based immunotherapeutic approaches in HCC.

Trial registration: ClinicalTrials.gov NCT01835223.

Keywords: CTL; NK cell; hepatocellular carcinoma; immunotherapy; viral hepatitis.

Figure 1

Shift in the balance between inhibitory and activation signaling; auxiliary methods for enhancing the therapeutic efficacy of NK cell-based immunotherapy. NK cells express a broad spectrum of receptors with activating or inhibitory functions and the balance between signaling inputs through these receptors shifts the equilibrium towards tolerance or activation of cytotoxicity against the target cells. (A). Under normal homeostatic condition, when the overall inhibitory signaling strength outweighs activating receptor signaling, NK cell activation is aborted resulting in tolerance. (B). During viral infection, cells upregulate stimulatory ligands for NK cell activating receptor NKG2D and as a result activation signal surpasses signaling through the inhibitory receptors KIRS and NKG2A, resulting in cytokine release and cytolysis of target cells. (C). Class I MHC ligands of NK cell inhibitory receptors are downregulated in tumor cells during malignant transformation and the loss of inhibitory signals causes positive signaling which leads to NK cell activation and tumor cell killing, referred to the “missing-self” phenomena. (D). Immune-checkpoint inhibitors could potentially relieve suppression of NK cell-mediated cytotoxicity by preventing inhibitory signaling through PD-1, CD6, NKG2A, and killer immunoglobulin-like receptors (KIRs). In addition, activation of members of the natural cytotoxicity receptor family, such as NKG2D, results in the release of preformed cytolytic granules containing granzyme B and perforin. Pro-inflammatory cytokines such as IL-12 and IL-18 enhance NK cell effector function and cytokine secretion, whereas anti-inflammatory cytokine TGFβ inhibits NK cell function. IL-15 is a crucial homeostatic cytokine for NK cells and exogenous IL-15 can cause NK cell activation. NK cells expressing Fc receptors for antibodies, can recognize and kill sensitized tumor cells through ADCC. Genetically modified CAR NK cells accelerate the antitumor activity of adoptive NK cell therapies.