Mistletoe-Extract Drugs Stimulate Anti-Cancer Vγ9Vδ2 T Cells

Human phosphoantigen-reactive V gamma 9V delta 2 T cells possess several characteristics, including MHC-independent recognition of tumor cells and potent killing potential, that make them attractive candidates for cancer immunotherapeutic approaches. Injectable preparations from the hemi-parasite plantViscum albumL. (European mistletoe) are commonly prescribed as complementary cancer therapy in European countries such as Germany, but their mechanism of action remains poorly understood. Here, we investigated in-depth the in vitro response of human T cells towards mistletoe-extract drugs by analyzing their functional and T-cell-receptor (TCR) response using flow cytometry and high-throughput sequencing respectively. Non-fermented mistletoe-extract drugs (AbnobaViscum), but not their fermented counterparts (Iscador), induced specific expansion of V gamma 9V delta 2 T cells among T cells. Furthermore, AbnobaViscum rapidly induced the release of cytotoxic granules and the production of the cytokines IFN gamma and TNF alpha in V gamma 9V delta 2 T cells. This stimulation of anti-cancer V gamma 9V delta 2 T cells was mediated by the butyrophilin BTN3A, did not depend on the accumulation of endogenous phosphoantigens and involved the same V gamma 9V delta 2 TCR repertoire as those of phosphoantigen-reactive V gamma 9V delta 2 T cells. These insights highlight V gamma 9V delta 2 T cells as a potential target for mistletoe-extract drugs and their role in cancer patients receiving these herbal drugs needs to be investigated.