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.
Subject(s)
CD28 Antigens/metabolism , CD8-Positive T-Lymphocytes/immunology , Lymphocytes, Tumor-Infiltrating/immunology , Ovarian Neoplasms/immunology , Receptors, Immunologic/metabolism , Adenocarcinoma, Mucinous/immunology , Adenocarcinoma, Mucinous/pathology , Animals , Apoptosis , Carcinoma, Endometrioid/immunology , Carcinoma, Endometrioid/pathology , Cell Survival , Cystadenocarcinoma, Serous/immunology , Cystadenocarcinoma, Serous/pathology , Cytotoxicity, Immunologic , Female , Humans , Ligands , Lymphocyte Activation , Mice , Mice, Inbred C57BL , NK Cell Lectin-Like Receptor Subfamily K , Ovarian Neoplasms/pathology , Receptors, Natural Killer CellABSTRACT
NKG2D serves as one of the most potent activating receptors for effector lymphocytes. in peripheral tissues. Here we report the characterization of Letal, the first human trans-membrane NKG2D ligand lacking an immunoglobulin-like alpha-3 ectodomain. Letal is constitutively expressed by a variety of normal tissues, and is upregulated in tumor cells of different origins. Unlike other NKG2D ligands, Letal mRNA expression progressively decreased after treatment of tumor cells with retinoic acid. Simultaneous T-cell receptor activation and engagement of Letal stimulated proliferation of CD8(+) cells and dramatically increased IL-2 and IFNgamma secretion. In addition, Letal induced the killing of cancer cells by CD8(+) and NK cells. These results suggest that Letal delivers activating signals to NK cells and promotes tumor immune surveillance by inducing the expansion of anti-tumor cytotoxic lymphocytes.