LETAL, A Tumor-Associated NKG2D Immunoreceptor Ligand, Induces Activation and Expansion of Effector Immune Cells

Conejo-Garcia, José R.; Benencia, Fabián; Courrèges, Marı́a C.; Khang, Eugene; Zhang, Lin; Mohamed-Hadley, Alisha; Vinocur, Jeffrey M.; Buckanovich, Ronald J.; Thompson, Craig B.; Levine, Bruce L.; Coukos, George

doi:10.4161/cbt.2.4.479

Cited by 57 publications

(55 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…NKG2D-mediated immune activation is triggered by an interaction with ligands [22,24] such as the MHC class I chain-related molecules (MICs) MICA and MICB [25], and the UL16-binding protein (ULBP) family [35][36][37]. In NK cells, the activation signal mediated by NKG2D dominates the inhibitory signals mediated by MHC class I binding to killer inhibitory receptors, leading to the lysis of target cells that express NKG2D ligands [22][23][24].…”

Section: Discussionmentioning

confidence: 99%

Decreased NKG2D expression on NK cells correlates with impaired NK cell function in patients with gastric cancer

2011

View full text Add to dashboard Cite

Background Although malignant diseases are known to be associated with immune suppression, the detailed mechanisms involved are still unknown. NKG2D is an activating cell surface receptor expressed by natural killer (NK) cells and CD8? T cells, and the engagement of NKG2D is extremely important for NK cell activation. Although decreased NKG2D expression on NK cells is closely related to immune evasion by some cancers, the immunopathological importance of this phenomenon in gastric cancer patients remains unclear. Methods NKG2D expression on NK cells was determined, using multicolor flow cytometry, to investigate the mechanisms responsible for immune evasion in gastric cancer patients. Results NKG2D expression on NK cells from gastric cancer patients was significantly lower than that in healthy controls. Also, NKG2D expression in advanced gastric cancer was significantly lower than that in early gastric cancer. NK cells from patients with lymph node metastasis expressed significantly lower levels of NKG2D than the NK cells from those without lymph node metastasis, and NKG2D expression on NK cells in gastric cancer tissue was significantly lower than that of circulating NK cells. NKG2D expression on NK cells obtained from cancer patients was restored after 48 h in culture with RPMI containing 10% AB serum. Furthermore, NKG2D expression on NK cells obtained after surgery was significantly higher than that before surgery.Conclusions Decreased NKG2D expression on NK cells may be one of the key mechanisms responsible for NK cell dysfunction in gastric cancer.

show abstract

Section: Discussionmentioning

confidence: 99%

Decreased NKG2D expression on NK cells correlates with impaired NK cell function in patients with gastric cancer

2011

View full text Add to dashboard Cite

show abstract

“…Letal (GenBank accession no. AY069961) was cloned from the ovarian carcinoma cell line A2008, as previously described (13). The entire Letal open reading frame was inserted in the MIGR1 retroviral vector upstream of GFP, preceded by an internal ribosome entry site (IRES), as previously described (13).…”

Section: Methodsmentioning

confidence: 99%

“…Letal expression was analyzed by TaqMan PCR analysis as described previously (13,15). The Letal system consisted of the following primers: Letal.F, 5Ј-CTCAGG-ATGCTCCTTTGTGACAT-3Ј, Letal.R, 5Ј-CTTCACGTTGACAAAACATC-TCG-3Ј; and the probe Letal.P, 5Ј-(FAM)CCCAGATAAAGACCAGTGATC-CTTCCACT(TAMRA)-3Ј.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Ovarian Carcinoma Expresses the NKG2D Ligand Letal and Promotes the Survival and Expansion of CD28− Antitumor T Cells

Conejo-Garcia¹,

Benencia²,

Courrèges³

et al. 2004

Cancer Research

Self Cite

View full text Add to dashboard Cite

The role of the NKG2D immunoreceptor and its ligands in antitumor immune response is incompletely understood. Here, we report that effector immune cells infiltrating ovarian carcinoma are mostly CD8؉ lymphocytes lacking CD28 but expressing the NKG2D costimulatory receptor. Human ovarian carcinoma expresses the novel NKG2D ligand lymphocyte effector cell toxicity-activating ligand (Letal). Letal was found to be an independent prognosticator of improved survival in advanced ovarian cancer. Higher levels of tumor-derived Letal were associated with stronger lymphocyte infiltration. Letal exerted marked costimulatory effects and induced type-1 polarization in CD8 ؉ CD28 -tumor-infiltrating lymphocytes ex vivo. Letal engagement increased the expression of the glucose transporter Glut-1, enhanced glucose up-take, and protected CD8؉ lymphocytes from cisplatin-induced killing. Letal also down-regulated the expression of Fas in CD8؉ cells and rendered them resistant to Fas ligand-induced apoptosis. Our results indicate that Letal promotes tumor immune surveillance by promoting the survival and intratumoral expansion of antitumor cytotoxic lymphocytes. We propose that Letal could be used for the ex vivo expansion of apoptosis-resistant tumorreactive cytotoxic lymphocytes for adoptive transfer.

show abstract

“…ULBP1 and ULBP2 were originally identified as glycoproteins interacting with the human cytomegalovirus (HCMV) protein UL16 [4]. Subsequently, four other human ULBP family members were identified based on sequence homology with ULBP1/ULBP2 or mouse Rae-1 molecules, respectively: ULBP3, ULBP4, RAET1G and RAET1L [5][6][7][8][9]. All these ULBP are encoded in a gene cluster on the long arm of human chromosome 6 (6q24.2-6q25.3), which is syntenic to a gene region on mouse chromosome 10 comprising the genes for the distantly related Rae-1 molecules.…”

Section: Introductionmentioning

confidence: 99%

Differential NKG2D binding to highly related human NKG2D ligands ULBP2 and RAET1G is determined by a single amino acid in the α2 domain

Wittenbrink

Spreu

Steinle³

2009

Eur J Immunol

View full text Add to dashboard Cite

The activating NK cell receptor NKG2D binds to numerous stress-induced cell surface glycoproteins with MHC class I-related ectodomains. In humans, NKG2D ligands (NKG2DL) are members of the MHC-encoded MIC and non-MHC-encoded ULBP families of proteins. The redundancy of NKG2DL raises questions about unique features associated with individual NKG2DL. The ULBP family member RAET1G contains an ectodomain highly related to ULBP2, but is unique by virtue of an extended cytoplasmic domain. Since RAET1G is poorly characterized, we studied expression and functional interactions of RAET1G in comparison to ULBP2. RAET1G transcripts were detected in most human tissues with an overall expression pattern similar to ULBP2. However, although ULBP2 strongly binds both NKG2D and the immunoevasive human cytomegalovirus glycoprotein UL16, RAET1G only weakly interacts with NKG2D and does not bind UL16. Differential binding capacities of the two highly related ectodomains are mainly due to a substitution of a conserved amino acid in the a2 domain of RAET1G. In functional terms, the reduced apparent avidity of RAET1G for NKG2D results in a less-efficient NKG2D down-regulation and NK degranulation. Altogether, RAET1G, like ULBP2, appears broadly expressed, but exhibits a lower apparent avidity for NKG2D due to a mutation in the center of the MHC-like fold.

show abstract

LETAL, A Tumor-Associated NKG2D Immunoreceptor Ligand, Induces Activation and Expansion of Effector Immune Cells

Cited by 57 publications

References 26 publications

Decreased NKG2D expression on NK cells correlates with impaired NK cell function in patients with gastric cancer

Decreased NKG2D expression on NK cells correlates with impaired NK cell function in patients with gastric cancer

Ovarian Carcinoma Expresses the NKG2D Ligand Letal and Promotes the Survival and Expansion of CD28− Antitumor T Cells

Differential NKG2D binding to highly related human NKG2D ligands ULBP2 and RAET1G is determined by a single amino acid in the α2 domain

Contact Info

Product

Resources

About