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.
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.
Hammond-McKibben
D M
DM
Department of Biology, College of Arts and Sciences, Virginia Polytechnic Institute and State University, Blacksburg 24061.
Seth
A
A
Nagarkatti
P S
PS
Nagarkatti
M
M
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
D015815:Cell Adhesion Molecules; D016207:Cytokines; D007376:Interleukin-2