Innate lymphocytes: pathogenesis and therapeutic targets of liver diseases and cancer

Abstract

The liver is a lymphoid organ with unique immunological properties, particularly, its predominant innate immune system. The balance between immune tolerance and immune activity is critical to liver physiological functions and is responsible for the sensitivity of this organ to numerous diseases, including hepatotropic virus infection, alcoholic liver disease, nonalcoholic fatty liver disease, autoimmune liver disease, and liver cancer, which are major health problems globally. In the past decade, with the discovery of liver-resident natural killer cells, the importance of innate lymphocytes with tissue residency has gradually become the focus of research. In this review, we address the current knowledge regarding hepatic innate lymphocytes with unique characteristics, including NK cells, ILC1/2/3s, NKT cells, γδ T cells, and MAIT cells, and their potential roles in liver homeostasis maintenance and the progression of liver diseases and cancer. A better understanding of the immunopathogenesis of hepatic innate lymphocytes will be helpful for proposing effective treatments for liver diseases and cancer.

TIGIT + TIM-3 + NK cells are correlated with NK cell exhaustion and disease progression in patients with hepatitis B virus‑related hepatocellular carcinoma

“…NK cells mediate immune surveillance and immune clearance functions in cancer. 5,6 In various malignant tumors such as lung cancer, 7 breast cancer, 8 head and neck cancer, 9 and liver cancer, 10 NK cells are immunosuppressed under the influence of the tumor microenvironment, which is an important cause of tumor progression and metastasis. Significantly elevated levels of inhibitory receptors mediate NK cell immunosuppression and exhaustion in liver cancer and other cancers, 11,12 such as T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT), Natural killer group 2 member A(NKG2A), T cell immunoglobulin domain and mucin domain protein-3 (TIM-3) and programmed cell death-1 (PD-1).…”

“…The enhanced activity of NK cells plays a vital role in the immune surveillance of HCC, which may be mediated by the production of perforin, Granzyme, and IFN-γ. 6 Meanwhile, the significant increase in the level of inhibitory receptors, the suppression of such NK cells is significantly associated with the progression of HCC. 16 The inhibitory receptor TIGIT is considered as an immune checkpoint that mainly mediates T cell exhaustion.…”

Innate lymphoid cells and cancer: Role in tumor progression and inhibition

“…However, in the last decades, accumulating evidences have documented that the multifaceted immunosuppressive processes ongoing in the TME lead to T‐cell dysfunction, which is implicated in the multiple tumor development [ 34 ]. Like T cells, the antitumor effects of NK cells are well‐established and extensively studied and reviewed in several publications [ 35 , 36 , 37 , 38 , 39 ]. In short, the mechanism of NK cell‐mediated antitumor effects is related to their cytolytic activity and cytokine production.…”

NLRP3 Deficiency in Hepatocellular Carcinoma Enhances Surveillance of NK-92 through a Modulation of MICA/B

“…NK cells are innate lymphocytes that can directly kill cancer or stressed cells. In human liver, nonparenchymal cells are composed of high-frequency NK and NKT cells (55%), except for parenchymal cells (termed hepatocytes) [19]. In addition, NK cells can be recruited into the liver [20], and they endow tumor cells with immune surveillance, such as cytokine production and natural cytotoxicity.…”