Immune Response of Human Propagated γδ-T-Cells to Neuroblastoma Recommend the Vδ1+ Subset for γδ-T-cell-based Immunotherapy

Human peripheral gamma delta-T-cells are able to induce cytolysis of neuroblastoma (Nb) tumor cells. Besides innate effector functions against infected cells and tumors, gamma delta-T-cells are involved in T-helper 1/T-helper 2 (T(H)1/T(H)2) differentiation of alpha beta-T-cells. However, as different gamma delta-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 V delta 1(+) and V delta 2(+) T cells in response to Nb. After short-term culture, both subsets released T(H)1 [interleukin (IL)-2, interferon (IFN)-gamma, IL-12, tumor necrosis factor (TNF)-alpha, TNF-beta)] and T(H)2 cytokines (IL-4, -5 -6, -10, -13 V delta 1 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 V alpha 2(+) than V delta 1(+) T cells. Nb challenge changed protein expression. T(H)2 cytokine and IFN-gamma release was blocked in both gamma delta-T-cell subsets. In V delta 2(+) gamma delta-T-Cells, T(H)1 cytokines were down-regulated and tumor growth-promoting factors (ANG, VEGF, EGF, and IGF-I) were strongly up-regulated. In contrast, V delta 1(+) gamma delta-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 V delta 1(+) rather than V delta 2(+) T cells support antitumor responses by secretion of proinflammatory cytokines. Furthermore, in contrast to other cell types, V delta 1(+) T cells do not sustain a growth-promoting or tolerogenic microenvironment. These data make V delta 1(+) T cells an ideal candidate for upcoming immunotherapy trials in Nb.