NKG2D Ligand Expression in Human Colorectal Cancer Reveals Associations with Prognosis and Evidence for Immunoediting

McGilvray, Roger; Eagle, Robert A.; Watson, Nicholas; Al‐Attar, Ahmad; Ball, Graham; Jafferji, Insiya; Trowsdale, John; Durrant, Lindy G.

doi:10.1158/1078-0432.ccr-09-0991

Cited by 156 publications

(159 citation statements)

References 42 publications

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“…25,26 We found that the NKG2D ligands, MICA/B and ULBP2, are expressed in about half of gastric tumors and that NKG2D ligand expression decreases according to the disease progression. The observed correlation with the disease stage and prognosis is consistent with data reported in colon cancer 27 and melanoma. 28 Although the exact mechanism behind the regulation of NKG2D ligand expression has not been fully elucidated, it is possible that expression of the ligand decreases Tumor Immunology in more advanced tumors as a result of immunoediting by NK killing or is associated with a distinct biology related to cell stress within the tumor microenvironment.…”

Section: Discussionsupporting

confidence: 90%

Therapeutic potential of highly cytotoxic natural killer cells for gastric cancer

et al. 2014

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To develop more effective therapies for patients with advanced gastric cancer, we examined the potential of ex vivo expanded natural killer (NK) cells. We assessed the expression of ligands for NK Group 2 Member D (NKG2D, an important NK activation molecule) in primary tumors from 102 patients with gastric cancer by immunohistochemistry and determined their prognostic value. We then examined the in vitro and in vivo cytotoxicity of NK cells from healthy donors and patients with gastric cancer. The cytotoxicity of resting and of interleukin (IL)-2-activated NK cells was compared to that of NK cells expanded for 7 days by coculture with the K562-mb15-4.1BBL cell line. As a result, the expression of NKG2D ligands in primary tumors was correlated with favorable presenting features and outcomes, suggesting that gastric cancer may be sensitive to NK cell cytotoxicity. Although resting NK cells showed minimal cytotoxicity against gastric cancer cells, K562-mb15-4.1BBL-expanded NK cells were highly cytotoxic and significantly more powerful than IL-2-activated NK cells. Cytotoxicity was correlated with NKG2D ligand expression and could be modulated by mitogen-activated protein kinase and AKT-PI3 kinase inhibitors. The cytotoxicity of expanded NK cells against HER2-positive gastric cancer cells could be increased by Herceptin and further augmented by Lapatinib. Finally, expanded NK cells exhibited strong antitumor activity in immunodeficient mice engrafted with a gastric cancer cell line. In conclusion, gastric cancer tumors express NKG2D ligands and are highly susceptible to killing by NK cells stimulated by K562-mb15-4.1BBL. These results provide a strong rationale for clinical testing of these NK cells in patients and suggest their use to augment the effects of antibody therapy.

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Section: Discussionsupporting

confidence: 90%

Therapeutic potential of highly cytotoxic natural killer cells for gastric cancer

et al. 2014

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“…For example, high tumour expression of MIC and/or ULBPs was associated with improved patient survival in colorectal cancer (McGilvray et al, 2009), whereas in ovarian cancer, high expression of several NKG2D ligands was inversely correlated with patient survival (McGilvray et al, 2010). Analysis of the NKG2D system in disease is complex because of the large number of distinct ligands for a single receptor and the possibility of regulation by released soluble ligands.…”

Section: Discussionmentioning

confidence: 99%

The human NKG2D ligand ULBP2 can be expressed at the cell surface with or without a GPI anchor and both forms can activate NK cells

Fernández-Messina

Ashiru

Agüera-González

et al. 2011

Journal of Cell Science

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SummaryThe activating immune receptor NKG2D binds to several stress-induced ligands that are structurally different. MHC-class-I-related chain (MIC) A/B molecules have a transmembrane domain, whereas most UL16 binding proteins (ULBPs) are glycosylphosphatidylinositol (GPI)-linked molecules. The significance of this variability in membrane anchors is unclear. Here, we demonstrate that ULBP2, but not ULBP1 or ULBP3, can reach the cell surface without the GPI modification. Several proteins are expressed at the cell surface as both transmembrane and GPI-linked molecules, either via alternative splicing or by the expression of linked genes. However, to our knowledge, ULBP2 is the first single mammalian cDNA that can be expressed as either a transmembrane or a GPI-anchored protein. The rate of maturation and the levels of cell surface expression of the non-GPI-linked form were lower than those of the GPIlinked ULBP2. Nonetheless, non-GPI ULBP2 was recognised by NKG2D and triggered NK cell cytotoxicity. These data show that differences in membrane attachment by NKG2D ligands are more important for regulation of their surface expression than for cytotoxic recognition by NKG2D and emphasise that detailed characterisation of the cell biology of individual NKG2D ligands will be necessary to allow targeted modulation of this system.

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“…In human colon cancers, high MHC class I-related chain expression on primary tumors is correlated with improved overall survival. 78 However, tumors may escape immune control in part through the shedding of NKG2D ligands, which induces downregulation of receptor expression and inhibition of NKG2D-dependent cytotoxicity. In patients with gastric cancer, the significant NKG2D downregulation on circulating CD8…”

Section: Cd45r0mentioning

confidence: 99%

Dual Roles for Immunity in Gastrointestinal Cancers

Ferrone

Dranoff²

2010

JCO

205

158

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Histopathologic examination reveals that most human tumors are associated with diverse immune cell infiltrates, but the roles of host reactions in disease pathogenesis and prognosis remain to be fully clarified. Recent investigations in genetically engineered murine tumor models have uncovered dual functions for immune responses during cancer development and progression. Alterations in tumor cell gene expression profiles and coding sequences may trigger the activation of cytotoxic lymphocytes, which act to restrain tumor growth. In contrast, persistent inflammatory reactions, which may be driven by infection, environmental toxins, or impaired immune regulation, create a microenvironment that fosters tumor cell growth, survival, invasion, and dissemination. The dynamic interplay of these competing responses appears to be a critical event in cancer pathogenesis, with tumor promotion and immune evasion proving dominant in clinically evident disease. Nonetheless, longitudinal studies of patient cohorts have demonstrated that particular histopathologic and genetic signatures of cytotoxic lymphocyte reactions provide important prognostic information. Here, we discuss the dual roles of immunity in cancer development, focusing on gastrointestinal malignancies, given the depth of recent insights into the mechanisms underlying these tumors.

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NKG2D Ligand Expression in Human Colorectal Cancer Reveals Associations with Prognosis and Evidence for Immunoediting

Cited by 156 publications

References 42 publications

Therapeutic potential of highly cytotoxic natural killer cells for gastric cancer

Therapeutic potential of highly cytotoxic natural killer cells for gastric cancer

The human NKG2D ligand ULBP2 can be expressed at the cell surface with or without a GPI anchor and both forms can activate NK cells

Dual Roles for Immunity in Gastrointestinal Cancers

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