The immunoreceptor NKG2D promotes tumour growth in a model of hepatocellular carcinoma

Abstract

Inflammation is recognized as one of the drivers of cancer. Yet, the individual immune components that possess pro- and anti-tumorigenic functions in individual cancers remain largely unknown. NKG2D is a potent activating immunoreceptor that has emerged as an important player in inflammatory disorders besides its well-established function as tumour suppressor. Here, we provide genetic evidence of an unexpected tumour-promoting effect of NKG2D in a model of inflammation-driven liver cancer. Compared to NKG2D-deficient mice, NKG2D-sufficient mice display accelerated tumour growth associated with, an increased recruitment of memory CD8+T cells to the liver and exacerbated pro-inflammatory milieu. In addition, we show that NKG2D contributes to liver damage and consequent hepatocyte proliferation known to favour tumorigenesis. Thus, the NKG2D/NKG2D-ligand pathway provides an additional mechanism linking chronic inflammation to tumour development in hepatocellular carcinoma. Our findings expose the need to selectively target the types of cancer that could benefit from NKG2D-based immunotherapy.

γδ T cells in cancer: a small population of lymphocytes with big implications

“…52 Tumor immune surveillance by activated murine cd T cells has been linked to their surface expression of the C-type lectin receptor NKG2D, ligands for which Rae-1 and H-60 (MICA and MICB in humans) are expressed at the surface of stressed cells. 55 While the authors did not look at the implication of cd T cells in this process, these cells could nevertheless play a role, given their enrichment in the liver and their robust cytokine expression in response to many inflammatory signals. 53 Upregulation of Rae-1 by epidermal cells induces activation and remodelling of DETCs from dendritic-to round-shaped cells, leading to a reorganisation of the epidermal architecture.…”

NKG2D‐ligands: Putting everything under the same umbrella can be misleading

“…100 Furthermore, a model in which NKG2D expression was associated with the promotion of tumour growth was reported. 101 These data emphasise the complex biology of this system and bring to light that not all tumours are equal and that not all the NKG2D-ligands work in the same manner. However, it should also be remembered that there are significant differences between the biology of the human and murine NKG2D/NKG2D-ligand systems that complicate extrapolation of observations made in experimental animals to human pathology.…”

“…Although essentially all the initial years of research on NKG2D showed the importance of this system for immune control of tumour initiation and progression both in vitro and in experimental mice; recently, new animal models have produced apparently contradictory results, for example, a shed form of the murine MULT1, a high‐affinity NKG2D‐ligand, caused NK cell activation and tumour rejection . Furthermore, a model in which NKG2D expression was associated with the promotion of tumour growth was reported . These data emphasise the complex biology of this system and bring to light that not all tumours are equal and that not all the NKG2D‐ligands work in the same manner.…”

Hepatocellular carcinoma: Prospects for natural killer cell immunotherapy

“…Sheppard et al further described the complex relationship of NKG2D and HCC, using NKG2D sufficient and deficient mouse models with chemically induced HCC. They show that NKG2D expression may correlate with tumour progression because of the promotion of a chronic inflammatory state . Similarly, seemingly contradictory evidence exists for other known activating NK cell receptors.…”

“…They show that NKG2D expression may correlate with tumour progression because of the promotion of a chronic inflammatory state. 74 Similarly, seemingly contradictory evidence exists for other known activating NK cell receptors. NKp30 is described as an activating receptor on NK cells.…”