The unique role of innate lymphoid cells in cancer and the hepatic microenvironment

Abstract

Cancer is a complex disease, and despite incredible progress over the last decade, it remains the leading cause of death worldwide. Liver cancers, including hepatocellular carcinoma (HCC), and liver metastases are distinct from other cancers in that they typically emerge as a consequence of long-term low-grade inflammation. Understanding the mechanisms that underpin inflammation-driven tissue remodeling of the hepatic immune environment is likely to provide new insights into much needed treatments for this devastating disease. Group 1 innate lymphoid cells (ILCs), which include natural killer (NK) cells and ILC1s, are particularly enriched in the liver and thought to contribute to the pathogenesis of a number of liver diseases, including cancer. NK cells are an attractive, but underexplored, therapeutic target in hepatic disease due to their role in immunosurveillance and their ability to recognize and eliminate malignant cells. ILC1s are closely related to and share many phenotypic features with NK cells but are less well studied. Thus, their utility in immunotherapeutic approaches is not yet well understood. Here, we review our current understanding of ILCs in cancer with a particular focus on liver and liver-related diseases.

Keywords: Cytokines; ILC subsets; Inflammation; Progenitors; Tumor.

Fig. 1

Receptor expression on mouse (top) and human (bottom) hepatic group 1 ILCs. Key transcription factors and the percentage of NK cells and ILC1s expressing each surface receptor

Fig. 2

Expression of transcription factors and their target genes in hepatic NK cells and ILC1s in mice. Eomes expression is unique to NK cells (purple) and induces the expression of genes that are involved in cytotoxicity, maturation and trafficking. Tbx21 is expressed by both cells (orange) and induces the expression of genes associated with cytotoxicity in both cell types and genes associated with maturation (Zeb2, Blimp1) and trafficking (S1pr5) in NK cells only, possibly due to the different expression levels or coregulation by other transcription factors. Znf683 is only expressed by ILC1s (teal) and regulates cytotoxicity and tissue retention

Fig. 3

Immune cell function in liver pathologies. A Liver cancer risk factors include alcohol-induced liver injury, which is associated with an increase in endotoxins in the liver that activate Kupffer cells to produce TNF-α and IL-6. This results in increased production of complement factors that drive an inflammatory environment. In pathogen infection, group 1 ILCs and cytotoxic T cells can recognize and eliminate infected hepatocytes. ILC1s can express PD-L1 in settings of chronic infection, which negatively regulates adaptive immune responses. Kupffer cells can be both proinflammatory and anti-inflammatory. Proinflammatory Kupffer cells produce TNF-α, and anti-inflammatory Kupffer cells produce TGF-β. Monocytes can regulate T cells to produce the proinflammatory cytokine IL-17. Obesity activates a cascade in which Kupffer cells produce TNF-α and IL-6, resulting in chronic inflammation and the development of fatty liver disease. B Chronic inflammation can lead to liver fibrosis. NK cells and ILC1s can directly recognize and eliminate activated stellate cells in the fibrotic liver, a pathway that can be inhibited by TGF-β secretion. C Sustained inflammation and fibrosis can result in the development of hepatocellular carcinoma. NK cells can directly kill cancerous cells but ultimately can become dysfunctional, for example, in response to TGF-β, which is highly expressed in hepatic inflammation. These dysfunctional NK cells express receptors that negatively regulate their cytotoxicity. CD49a⁺ ILC1s can inhibit NK cell function and promote cancer growth by producing proangiogenic factors allowing tumor growth

Fig. 4

The function of group 1 ILCs in experimental liver metastases in mice. NK cells depend on IL-15 for their activation and exhibit immunosurveillance and cytotoxicity that allow them to actively drive antitumor functions. Although NK cells can eliminate tumor cells to control potential tumor metastasis, they can become dysfunctional within the cytokine milieu of the tumor microenvironment, which results in reduced killing of abnormal cells compared with naïve NK cells. In contrast to NK cells, ILC1s do not appear to readily infiltrate metastatic tumors to directly eliminate them but can control metastatic seeding by producing granzyme B and IFN-γ. The fact that they do not penetrate within the tumor spatially positions them distant from the immunosuppressive environment of the tumor, allowing them to retain their antimetastatic functions. Their development and antitumor functions rely on their expression of the transcription factor RORα. A recently described intermediate ILC1/NK cell type, CD49a⁺CD49b⁺Eomes⁺ cells, are present within nodules and produce high levels of granzyme B [94]. Although their role in tumors has not yet been fully elucidated, mice deficient in TGF-β signaling fail to develop CD49a⁺CD49b⁺Eomes⁺ cells and present with fewer metastases, suggesting a protumor function of these cells despite their high production of granzyme B