Human γδ T cells induce CD8+ T cell antitumor responses via antigen-presenting effect through HSP90-MyD88-mediated activation of JNK

Human V gamma 9V delta 2 T cells have attracted considerable attention as novel alternative antigen-presenting cells (APCs) with the potential to replace dendritic cells in antitumor immunotherapy owing to their high proliferative capacity and low cost. However, the utility of gamma delta T cells as APCs to induce CD8(+) T cell-mediated antitumor immune response, as well as the mechanism by which they perform APC functions, remains unexplored. In this study, we found that activated V gamma 9V delta 2 T cells were capable of inducing robust CD8(+) T cell responses in osteosarcoma cells. Activated gamma delta T cells also effectively suppressed osteosarcoma growth by priming CD8(+) T cells in xenograft animal models. Mechanistically, we further revealed that activated gamma delta T cells exhibited increased HSP90 production, which fed back to upregulate MyD88, followed by JNK activation and a subsequent improvement in CCL5 secretion, leading to enhanced CD8(+) T cell cross-priming. Thus, our study suggests that V gamma 9V delta 2 T cells represent a promising alternative APC for the development of gamma delta T cell-based tumor immunotherapy.