Receptors and lytic mediators regulating anti-tumor activity by the leukemic killer T cell line TALL-104.
The major histocompatibility complex nonrestricted cytotoxic leukemic T cell line T acute lymphoblastic leukemia (TALL)-104 is being pursued as a therapeutic agent for cancer. However, the receptors and effector mechanisms responsible for its broad tumoricidal function remain undefined. Here, we examined the roles played by natural cytotoxicity receptors (NCR), killer cell immunoglobulin-like receptors, cytolytic granule components, and tumor necrosis factor (TNF) family members in tumor recognition and lysis by TALL-104 cells. The perforin-granzyme pathway, TNF-related apoptosis-inducing ligand (TRAIL), and Fas were each involved in the lysis of particular tumor targets by TALL-104. Furthermore, phorbol 12-myristate 13-acetate/ionomycin treatment induced surface expression of Fas-L and TRAIL. In addition, supernatants from CD3-stimulated TALL-104 cultures exhibited antiproliferative activity, which was blocked 50-90% by anti-TNF-alpha monoclonal antibody (mAb). Although negative for the NCR natural killer (NK)p44, this cell line was found to express NKp46. An anti-NKp46 antibody strongly blocked TALL-104-mediated lysis of certain targets and directly induced cytokine production, granule release, and redirected lysis responses. Anti-NKG2D and anti-2B4 also stimulated redirected cytotoxicity by TALL-104. By contrast, anti-NKG2A mAb did not stain the cells or inhibit killing responses. Alternatively, KIR3DL2 was detected on TALL-104, and expression of its reported ligand, human leukocyte antigen (HLA)-A, on target cells provided protection from cytotoxicity. Thus, NKp46, NKG2D, and 2B4 are activating receptors, and KIR3DL2 is an inhibitory receptor on TALL-104. The data demonstrate the ability of TALL-104 cells to recognize a wide variety of tumors with NK cell receptors and kill them with a broad arsenal of cytolytic effector mechanisms, including cytolytic granules and TNF family ligands.
Brando
Clara
C
The Wistar Institute, Philadelphia, PA, USA.
Mukhopadhyay
Sunil
S
Kovacs
Eniko
E
Medina
Rosa
R
Patel
Pritesh
P
Catina
Tracey L
TL
Campbell
Kerry S
KS
Santoli
Daniela
D
D019264:Adoptive Transfer; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D015703:Antigens, CD / Q000276:immunology; D051017:Apoptosis Regulatory Proteins; D017252:CD3 Complex / Q000276:immunology; D002273:Carcinogens / Q000494:pharmacology; D015550:Cell Degranulation / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects / Q000276:immunology*; D053222:Fas Ligand Protein; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D017874:Immediate-Early Proteins / Q000276:immunology; D015759:Ionomycin / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D019169:Jurkat Cells; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000276:immunology; D020559:Monomeric GTP-Binding Proteins / Q000276:immunology; D055654:NK Cell Lectin-Like Receptor Subfamily C; D055655:NK Cell Lectin-Like Receptor Subfamily K; D055627:Natural Cytotoxicity Triggering Receptor 1; D009369:Neoplasms / Q000276:immunology / Q000628:therapy; D011971:Receptors, Immunologic / Q000276:immunology; D054340:Receptors, KIR; D054347:Receptors, KIR3DL2; D055607:Receptors, Natural Killer Cell; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D000071176:Signaling Lymphocytic Activation Molecule Family; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology*; D053221:TNF-Related Apoptosis-Inducing Ligand; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D048069:Tumor Necrosis Factors / Q000276:immunology; D020298:U937 Cells
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; C084093:CD244 protein, human; D017252:CD3 Complex; D002273:Carcinogens; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D015395:Histocompatibility Antigens Class I; D017874:Immediate-Early Proteins; D007476:Ionophores; C515084:KIR3DL2 protein, human; C527054:KLRC1 protein, human; C527085:KLRK1 protein, human; D008562:Membrane Glycoproteins; C112260:NCR1 protein, human; D055654:NK Cell Lectin-Like Receptor Subfamily C; D055655:NK Cell Lectin-Like Receptor Subfamily K; D055627:Natural Cytotoxicity Triggering Receptor 1; D011971:Receptors, Immunologic; D054340:Receptors, KIR; D054347:Receptors, KIR3DL2; D055607:Receptors, Natural Killer Cell; D000071176:Signaling Lymphocytic Activation Molecule Family; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D048069:Tumor Necrosis Factors; D015759:Ionomycin; C490245:GEM protein, human; D020559:Monomeric GTP-Binding Proteins; D013755:Tetradecanoylphorbol Acetate