Glioblastoma Cells Potentiate The Induction Of The Th1-Like Profile In Phosphoantigen-Stimulated Gamma Delta T Lymphocytes

Purpose gamma delta T lymphocytes are non-conventional T cells that participate in protective immunity and tumor surveillance. In healthy humans, the main subset of circulating gamma delta T cells express the TCRV gamma 9V delta 2. This subset responds to non-peptide prenyl-pyrophosphate antigens such as (E)-4-hydroxy-3-methyl-but-enyl pyrophosphate (HMBPP). This unique feature of V gamma 9V delta 2 T cells makes them a candidate for anti-tumor immunotherapy. In this study, we investigated the response of HMBPP-activated V gamma 9V delta 2 T lymphocytes to glioblastoma multiforme (GBM) cells.Methods Human purified gamma delta T cells were stimulated with HMBPP (1 mu M) and incubated with GBM cells (U251, U373 and primary GBM cultures) or their conditioned medium. After overnight incubation, expression of CD69 and perforin was evaluated by flow cytometry and cytokines production by ELISA. As well, we performed a meta-analysis of transcriptomic data obtained from The Cancer Genome Atlas.Results HMBPP-stimulated gamma delta T cells cultured with GBM or its conditioned medium increased CD69, intracellular perforin, IFN-gamma, and TNF-alpha production. A meta-analysis of transcriptomic data showed that GBM patients display better overall survival when mRNA TRGV9, the V gamma 9 chain-encoding gene, was expressed in high levels. Moreover, its expression was higher in low-grade GBM compared to GBM. Interestingly, there was an association between gamma delta T cell infiltrates and TNF-alpha expression in the tumor microenvironment.Conclusion GBM cells enhanced Th1-like profile differentiation in phosphoantigen-stimulated gamma delta T cells. Our results reinforce data that have demonstrated the implication of V gamma 9V delta 2 T cells in the control of GBM, and this knowledge is fundamental to the development of immunotherapeutic protocols to treat GBM based on gamma delta T cells.