Activation and growth of murine tumor-specific T-cells which have in vivo activity with bryostatin 1.
We examined the ability of bryostatin 1 (Bryo), a novel protein kinase C activator, plus ionomycin (Io), a calcium ionophore, to activate T-cells with specific antitumor activity. Lymphocytes from the draining lymph nodes (DLN) of MCA-105 tumor-bearing host mice were stimulated with Bryo/Io, either fresh or after in vitro stimulation with autologous tumor, and then were incubated in interleukin-2 at 20 units/ml. Lymphocytes sensitized with tumor cells in vitro and then stimulated with Bryo/Io exhibited significant expansion (12-fold) after a total of 3 weeks in culture and moderate cytolytic activity (40% at an effector:tumor cell ratio of (80:1) and were exclusively CD8+ T-cells. DLN cells activated immediately with Bryo/Io, without tumor antigen sensitization in vitro, displayed marked growth (130-fold expansion) over 3 weeks in culture, had weak cytolytic activity (8% at an effector:tumor ratio of 80:1), and were a mixed population of CD8+ and CD4+ cells. Despite the differences in phenotypes and in cytotoxicity, both groups of DLN cells were highly effective in vivo against MCA-105 pulmonary metastases. Bryo/Io-activated DLN cells from MCA-105 tumor-bearing hosts had no therapeutic efficacy against B16 melanoma or MCA-203 sarcoma metastases. Lymph node cells from normal mice and non-draining lymph node cells from tumor-bearing hosts could be expanded with Bryo/Io to a degree similar to that of DLN cells but had no antitumor activity. Phenotypic analyses and in vitro and in vivo depletion studies demonstrate that CD8+ cells mediated tumor regression.
Tuttle
T M
TM
Department of Surgery, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298.
Inge
T H
TH
Bethke
K P
KP
McCrady
C W
CW
Pettit
G R
GR
Bear
H D
HD
D000818:Animals; D000911:Antibodies, Monoclonal; D000954:Antigens, Surface / Q000032:analysis; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D054713:Bryostatins; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D005260:Female; D016219:Immunotherapy, Adoptive; D007783:Lactones / Q000494:pharmacology* / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000276:immunology / Q000556:secondary / Q000628:therapy; D008213:Lymphocyte Activation; D008212:Lymphocyte Depletion; D018942:Macrolides; D008546:Melanoma, Experimental; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000276:immunology / Q000628:therapy*; D010641:Phenotype; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*
D000911:Antibodies, Monoclonal; D000954:Antigens, Surface; D000970:Antineoplastic Agents; D054713:Bryostatins; D007783:Lactones; D018942:Macrolides; C046785:bryostatin 1