Human gammadelta T cells as mediators of chimaeric-receptor redirected anti-tumour immunity.
Human peripheral blood gammadelta T cells (Vgamma9(+) Vdelta2(+)) can be selectively expanded in vivo by the systemic administration of aminobisphosphonates without prior antigen priming. To assess the potential of human gammadelta T cells to serve as effector cells of specific anti-tumour immunity, we expanded peripheral blood-derived gammadelta T cells and transduced them with recombinant retrovirus encoding G(D2)- or CD19-specific chimaeric receptors. Flow cytometric analysis of T cells from four individual donors cultured in the presence of zoledronate at day 14 of culture showed selective enrichment of the gammadelta T cell population (Vgamma9(+) Vdelta2(+) CD3(+) CD4(-) CD8(-)) to 73-96% of total CD3(+) T cells. Retroviral gene transfer resulted in chimaeric receptor surface expression in 73 +/- 12% of the population. Transduced gammadelta T cells efficiently recognized antigen-expressing tumour cell targets, as demonstrated by target-specific upregulation of CD69 and secretion of interferon-alpha. Moreover, transduced gammadelta T cells efficiently and specifically lysed the antigen-expressing tumour targets. They could be efficiently expanded in vitro and maintained in culture for prolonged periods. Zoledronate-activated human gammadelta T cells expressing chimaeric receptors may thus serve as potent and specific anti-tumour effector cells. Their responsiveness to stimulation with aminobisphosphonates may enable the selective re-expansion of adoptively transferred T cells in vivo, permitting long lasting anti-tumour immune control.
Department of Paediatric Haematology and Oncology, University Children's Hospital Münster, Münster, Germany.
Markus
M
Rischer
Sibylle
S
Pscherer
Susanne
S
Duwe
Josef
J
Vormoor
Heribert
H
Jürgens
Claudia
C
Rossig
D000951:Antigens, Neoplasm / Q000276:immunology; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D004164:Diphosphonates / Q000494:pharmacology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D016130:Immunophenotyping; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007371:Interferon-gamma / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000276:immunology; D009369:Neoplasms / Q000276:immunology*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000097:blood*; D012190:Retroviridae / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology*; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured; D000077211:Zoledronic Acid
D000951:Antigens, Neoplasm; D004164:Diphosphonates; D018984:Epitopes, T-Lymphocyte; D007093:Imidazoles; D016692:Receptors, Antigen, T-Cell, gamma-delta; D000077211:Zoledronic Acid; D007371:Interferon-gamma