title: Characterization of factors regulating successful immunotherapy using a tumor-specific cytotoxic T lymphocyte clone: role of interleukin-2, cycling pattern of lytic activity and adhesion molecules.
abstract: Adoptive immunotherapy against cancer has met with varying degrees of success, the reasons for which remain unclear. The present study characterizes factors that regulate successful immunotherapy of mice bearing a syngeneic T-cell lymphoma, designated LSA, using a tumor-specific cytotoxic T lymphocyte (CTL) clone, PE-9. Adoptive transfer of PE-9 cells afforded significant protection in normal but not in nude mice against LSA tumor. However, the PE-9 cells could protect the nude mice when injected along with normal CD4+ T cells. Administration of IL-2 along with PE-9 cells failed to enhance tumor immunotherapy. IL-2 therapy was toxic inasmuch as injection of the CTL clone PE-9 + IL-2, but not PE-9 or IL-2 alone, for 5 days into irradiated mice caused vascular leak syndrome (VLS). PE-9 cells cultured with high doses of rIL-2 in vitro also caused TCR-independent and MHC-unrestricted lysis of SV40-transformed endothelial cells. Furthermore, PE-9 cells cultured in vitro for 24-96 hr with IL-2 exhibited cycling pattern of tumor-specific cytotoxicity with maximum cytotoxicity demonstrable at 48 hr and virtually no cytolytic activity at 96 hr of culture or thereafter. The loss of cytotoxicity correlated with down-regulation of several adhesion molecule expressions on PE-9 cells, particularly the alpha beta-TCR, as well as the mRNA for TNF-alpha, IFN-gamma and perforin, although the levels of granzyme A were not altered. Interestingly, the outcome of immunotherapy by PE-9 cells depended on the cycling pattern of cytotoxicity. Our data suggest that successful immunotherapy against cancer using a CTL clone depends on several factors, such as the cycling pattern of lytic activity, density of adhesion molecules, levels of cytokines expressed and the ability of IL-2 and CTL to trigger VLS.
authors.affiliation: Department of Biology, College of Arts and Sciences, Virginia Polytechnic Institute and State University, Blacksburg 24061.
authors.forename: D M
authors.initials: DM
authors.lastname: Hammond-McKibben
authors.forename: A
authors.initials: A
authors.lastname: Seth
authors.forename: P S
authors.initials: PS
authors.lastname: Nagarkatti
authors.forename: M
authors.initials: M
authors.lastname: Nagarkatti
mesh_terms: D000818:Animals; D001483:Base Sequence; D015815:Cell Adhesion Molecules / Q000096:biosynthesis / Q000276:immunology; D002999:Clone Cells / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D004727:Endothelium / Q000166:cytology; D005260:Female; D016130:Immunophenotyping; D016219:Immunotherapy, Adoptive; D007376:Interleukin-2 / Q000276:immunology / Q000627:therapeutic use*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D016399:Lymphoma, T-Cell / Q000628:therapy*; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D012074:Remission Induction; D013045:Species Specificity; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
chemical_list: D015815:Cell Adhesion Molecules; D016207:Cytokines; D007376:Interleukin-2