title: Ovarian carcinoma expresses the NKG2D ligand Letal and promotes the survival and expansion of CD28- antitumor T cells.
abstract: 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 tumor-reactive cytotoxic lymphocytes for adoptive transfer.
authors.affiliation: Center for Research in Reproduction and Women's Health, University of Pennsylvania Medical Center, 421 Curie Boulevard, Philadelphia, PA 19104, USA.
authors.forename: Jose R
authors.initials: JR
authors.lastname: Conejo-Garcia
authors.forename: Fabian
authors.initials: F
authors.lastname: Benencia
authors.forename: Maria C
authors.initials: MC
authors.lastname: Courreges
authors.forename: Phyllis A
authors.initials: PA
authors.lastname: Gimotty
authors.forename: Eugene
authors.initials: E
authors.lastname: Khang
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Buckanovich
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Frauwirth
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.forename: Dionyssios
authors.initials: D
authors.lastname: Katsaros
authors.forename: Craig B
authors.initials: CB
authors.lastname: Thompson
authors.forename: Bruce
authors.initials: B
authors.lastname: Levine
authors.forename: George
authors.initials: G
authors.lastname: Coukos
mesh_terms: D002288:Adenocarcinoma, Mucinous / Q000276:immunology / Q000473:pathology; D000818:Animals; D017209:Apoptosis; D018106:CD28 Antigens / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D018269:Carcinoma, Endometrioid / Q000276:immunology / Q000473:pathology; D002470:Cell Survival; D018284:Cystadenocarcinoma, Serous / Q000276:immunology / Q000473:pathology; D003602:Cytotoxicity, Immunologic; D005260:Female; D006801:Humans; D008024:Ligands; D008213:Lymphocyte Activation; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D055655:NK Cell Lectin-Like Receptor Subfamily K; D010051:Ovarian Neoplasms / Q000276:immunology* / Q000473:pathology; D011971:Receptors, Immunologic / Q000378:metabolism*; D055607:Receptors, Natural Killer Cell
chemical_list: D018106:CD28 Antigens; C527085:KLRK1 protein, human; C527086:Klrk1 protein, mouse; D008024:Ligands; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell