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.
Highlights
Inflammation is recognized as one of the drivers of cancer
NKG2D recognizes a large repertoire of ligands related to MHC class I molecules including MICA, MICB and the ULBP1-6 family of molecules in humans; MULT1 and several isoforms of RAE-1 and H60 in mice[5]
Cohorts of DEN-treated Klrk[1] þ / þ (NKG2D-WT) mice, Klrk[1] À / À (NKG2D-KO) mice and untreated age-match control (AMC) mice were assessed over time for clinical signs of illness
Summary
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-expressing cells are believed to reject neoplastic cells at early stages of tumorigenesis[3], before the occurrence of immunoediting—the process by which tumour variants deprived of ligands evade immune surveillance[14]. While in vitro studies and in vivo transplanted tumour models have shown that NK cells and activated CD8 þ T cells can effectively reject tumour transfectants expressing NKG2D ligands[15,16,17], evidence for NKG2D function in long-term models that recapitulate the complexity of the tumour microenvironment in human cancer are scarce[4,18]. NKG2D has been shown to contribute to certain inflammatory disorders[19,20], autoimmune diseases[21,22,23,24] and wound associated inflammation[25], which constitute a favourable ground for tumour initiation and progression. A comprehensive understanding of the cell types, cytokines and chemokines involved in this process is far from elucidated and whether NKG2D aids the generation of protumorigenic inflammation is not known
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