Synthetic phosphoantigens enhance human Vγ9Vδ2 T lymphocytes killing of non-Hodgkin's B lymphoma

Background: Non-Hodgkin's B lymphomas (NI-IL) are often resistant to conventional treatments and, until now, immunotherapeutic approaches against NHL only aimed at inducing alpha beta anti-tumor effectors. Nevertheless, human blood V gamma 9V delta2 T lymphocytes represent an abundant pool of cytotoxic tumor-reactive cells. V gamma 9V delta2 T cells are strongly activated by natural compounds, from which powerful synthetic ligands have been derived. These synthetic antigens induce efficient V gamma 9V delta2 T cell responses in vitro. Materials and Methods: We set up a series of V gamma 9V delta2 T cell-activation experiments, including cytotoxic activity and amplification from whole blood cells. Several types of V gamma 9V delta2 effectors were challenged against a panel of 16 B lymphoma cell lines. These tests have been performed in the absence and presence of gamma delta -speciflc synthetic ligands to evaluate the effect of such molecules on gamma delta anti-tumor activity. Results: We report here that V gamma 9V delta2 T cells recognize B lymphomas. This recognition is associated with the cytotoxic activity against B-lymphoma cells and/or proliferative responses, and appears to be T-cell antigen receptor (TCR) -dependent. Because few B lymphoma induce a complete set of V gamma 9V delta2 cell responses, a chemical ligand of V gamma 9V delta2 T cells was used to enhance both proliferation and cytotoxic activity of anti-B lymphoma effectors. We show that such synthetic compound improves V gamma 9V delta2 CTL numbers and lysis of B lymphoma lines, especially when the targets are already spontaneously recognized by these effectors. Conclusions: We report here that human V gamma 9V delta2 T cells anti-B lymphoma response can be improved by use of specific synthetic ligands, which enhance their cytotoxic activity and allows their rapid expansion ex vivo.