7 results found
Sheppard S, Santosa EK, Lau CM, et al., 2021, Lactate dehydrogenase A-dependent aerobic glycolysis promotes natural killer cell anti-viral and anti-tumor function, Cell Reports, Vol: 35, Pages: 109210-109210, ISSN: 2211-1247
Wiedemann GM, Santosa EK, Grassmann S, et al., 2021, Deconvoluting global cytokine signaling networks in natural killer cells, Nature Immunology, Vol: 22, Pages: 627-638, ISSN: 1529-2908
Sheppard S, Sun JC, 2021, Virus-specific NK cell memory, Journal of Experimental Medicine, Vol: 218, ISSN: 0022-1007
<jats:p>NK cells express a limited number of germline-encoded receptors that identify infected or transformed cells, eliciting cytotoxicity, effector cytokine production, and in some circumstances clonal proliferation and memory. To maximize the functional diversity of NK cells, the array and expression level of surface receptors vary between individual NK cell “clones” in mice and humans. Cytomegalovirus infection in both species can expand a population of NK cells expressing receptors critical to the clearance of infected cells and generate a long-lived memory pool capable of targeting future infection with greater efficacy. Here, we discuss the pathways and factors that regulate the generation and maintenance of effector and memory NK cells and propose how this understanding may be harnessed therapeutically.</jats:p>
The activating receptor NKG2D and its ligands are recognized as a potent immune axis that controls tumor growth and microbial infections. With regards to cancer surveillance, various studies have demonstrated the antitumor function mediated by NKG2D on natural killer cells and on conventional and unconventional T cells. The use of NKG2D-deficient mice established the importance of NKG2D in delaying tumor development in transgenic mouse models of cancer. However, we recently demonstrated an unexpected, flip side to this coin, the ability for NKG2D to contribute to tumor growth in a model of inflammation-driven liver cancer. With a focus on the liver, here, we review current knowledge of NKG2D-mediated tumor surveillance and discuss evidence supporting a dual role for NKG2D in cancer immunity. We postulate that in certain advanced cancers, expression of ligands for NKG2D can drive cancer progression rather than rejection. We propose that the nature of the microenvironment within and surrounding tumors impacts the outcome of NKG2D activation. In a form of autoimmune attack, NKG2D promotes tissue damage, mostly in the inflamed tissue adjacent to the tumor, facilitating tumor progression while being ineffective at rejecting transformed cells in the tumor bed.
Sheppard S, Schuster IS, Andoniou CE, et al., 2018, The murine natural cytotoxic receptor NKp46/NCR1 controls TRAIL protein expression in NK cells and ILC1, Cell Reports, Vol: 22, Pages: 3385-3392, ISSN: 2211-1247
TRAIL is an apoptosis-inducing ligand constitutively expressed on liver resident type 1 innate lymphoid cells (ILC1) and a subset of Natural Killer (NK) cells where it contributes to NK cell anti-tumor, anti-viral and immunoregulatory functions. Yet the intrinsic pathways involved in TRAIL expression in ILC remain unidentified. Here we demonstrate that the murine natural cytotoxic receptor mNKp46/NCR1, expressed on ILC1 and NK cells, controls TRAIL protein expression. Using NKp46-deficient mice, we show that liver ILC1 lack constitutive expression of TRAIL protein and that NK cells activated in vitro and in vivo fail to upregulate cell-surface TRAIL in the absence of NKp46. We show that NKp46 regulates TRAIL expression in a dose-dependent manner and that the reintroduction of NKp46 in mature NK cells deficient for NKp46 is sufficient to restore TRAIL surface expression. These studies uncover a link between NKp46 and TRAIL expression in ILC with potential implications in pathologies involving NKp46-expressing cells.
Sheppard S, Guedes J, Mroz A, et al., 2017, The immunoreceptor NKG2D promotes tumour growth in a model of hepatocellular carcinoma, Nature Communications, Vol: 8, ISSN: 2041-1723
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.
Sheppard S, Triulzi C, Ardolino M, et al., 2013, Characterization of a novel NKG2D and NKp46 double-mutant mouse reveals subtle variations in the NK cell repertoire, BLOOD, Vol: 121, Pages: 5025-5033, ISSN: 0006-4971
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