Immune response of human propagated gammadelta-T-cells to neuroblastoma recommend the Vdelta1+ subset for gammadelta-T-cell-based immunotherapy.
Human peripheral gammadelta-T-cells are able to induce cytolysis of neuroblastoma (Nb) tumor cells. Besides innate effector functions against infected cells and tumors, gammadelta-T-cells are involved in T-helper 1/T-helper 2 (TH1/TH2) differentiation of alphabeta-T-cells. However, as different gammadelta-T-cell subsets vary considerably in their functional properties, the aim of the present study was to define repertoires of cytokines, chemokines, and angiogenic factors of in vitro expanded Vdelta1+ and Vdelta2+ T cells in response to Nb. After short-term culture, both subsets released TH1 [interleukin (IL)-2, interferon (IFN)-gamma, IL-12, tumor necrosis factor (TNF)-alpha, TNF-beta)] and TH2 cytokines (IL-4, -5, -6, -10, -13, Vdelta1 also transforming growth factor (TGF)-beta, chemokines (I-309, monocyte chemotactic protein (MCP)-1-3, regulated upon activation, normal T-cell expressed and secreted), ILs (IL-1, -8, -15), cytokines (leptin) as well as angiogenic growth factors [angiogenin (ANG), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), Insulin-like growth factor (IGF)-I]. These molecules were expressed at higher levels in Vdelta2+ than Vdelta1+ T cells. Nb challenge changed protein expression. TH2 cytokine and IFN-gamma release was blocked in both gammadelta-T-cell subsets. In Vdelta2 gammadelta-T-cells, TH1 cytokines were down-regulated and tumor growth-promoting factors (ANG, VEGF, EGF, and IGF-I) were strongly up-regulated. In contrast, Vdelta1+ gammadelta-T-cells stopped the release of tumor-supportive factors and tolerogenic TGF-beta, and strongly up-regulated TNF-alpha, TNF-beta, MCP-1 and -2 and maintained their IL-2 production. In summary, our data show that after being challenged with Nb cells, propagated Vdelta1+ rather than Vdelta2+ T cells support antitumor responses by secretion of proinflammatory cytokines. Furthermore, in contrast to other cell types, Vdelta1+ T cells do not sustain a growth-promoting or tolerogenic microenvironment. These data make Vdelta1+ T cells an ideal candidate for upcoming immunotherapy trials in Nb.
Schilbach
Karin
K
Department of Pediatric Stem Cell Transplantation, University Children's Hospital, University of Tübingen, Tübingen, Germany. karin.schilbach@med.uni-tuebingen.de
Frommer
Klaus
K
Meier
Sybille
S
Handgretinger
Rupert
R
Eyrich
Matthias
M
D002454:Cell Differentiation; D045744:Cell Line, Tumor; D019070:Cell Lineage; D002465:Cell Movement; D016207:Cytokines / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D020869:Gene Expression Profiling; D006801:Humans; D007113:Immunity, Innate; D009447:Neuroblastoma / Q000276:immunology* / Q000473:pathology; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D019139:Tumor Escape
D016207:Cytokines; D016692:Receptors, Antigen, T-Cell, gamma-delta; C521523:T-cell receptor Vdelta2, human