Bryostatin 1 activates T cells that have antitumor activity.
Several strategies have been used to stimulate the growth of tumor-specific T cells in place of tumor antigen. One approach is to use pharmacologic agents to activate the second messenger pathways of T-cell activation. In the present study, we examined the ability of the protein kinase C activator bryostatin 1 (B) plus the calcium ionophore ionomycin (I) to stimulate the growth of lymphocytes obtained from the axillary lymph nodes (DLN) draining a progressively growing intradermal plasmacytoma tumor. Draining lymph node cells were initially cultured with autologous tumor cells and 20 U/ml of interleukin-2 (IL-2) for 7 days. The lymphocytes were then incubated with various concentrations of bryostatin 1 plus 1 microM ionomycin and cultured for an additional 14 days in IL-2. DLN cells initially cultured with autologous tumor and then restimulated with 5 nM bryostatin 1 and 1 microM ionomycin exhibited marked in vitro proliferation and 15-fold expansion of cell numbers over 2 weeks. The cells expanded with B/I were predominantly CD8+ T cells and retained specific in vitro cytotoxicity against autologous tumor. When adoptively transferred to mice with established liver metastases, DLN cells restimulated with B/I-mediated specific tumor regression.
Tuttle
T M
TM
Department of Surgery, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298.
Inge
T H
TH
Wirt
C P
CP
Frank
J L
JL
McCrady
C M
CM
Bear
H D
HD
D000818:Animals; D054713:Bryostatins; D004789:Enzyme Activation / Q000187:drug effects; D016219:Immunotherapy, Adoptive; D015759:Ionomycin / Q000494:pharmacology; D007783:Lactones / Q000494:pharmacology*; D008198:Lymph Nodes / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D018942:Macrolides; D012515:Mast-Cell Sarcoma / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008811:Mice, Inbred DBA; D011493:Protein Kinase C / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects* / Q000276:immunology
D054713:Bryostatins; D007783:Lactones; D018942:Macrolides; C046785:bryostatin 1; D015759:Ionomycin; D011493:Protein Kinase C