Targeting myeloma-osteoclast interaction with Vγ9Vδ2 T cells

Abstract

Multiple myeloma (MM) cells stimulate osteoclastogenesis, and osteoclasts (OCs) in turn enhance MM growth and drug resistance, resulting in a vicious cycle. Vγ9Vδ2 T cells exert potent anti-tumor effects, making T cell-based immunotherapies using these cells attractive candidates for currently incurable malignancies, such as MM. However, the impact of such treatments on the MM-OC interaction is largely unknown. We demonstrate here that Vγ9Vδ2 T cells expanded by zoledronic acid and IL-2 exerted potent cytotoxic effects on both MM cells and OCs, even in coculture settings, but showed no such effect on bone marrow stromal cells. Vγ9Vδ2 T cells marginally affected colony formation from normal hematopoietic progenitors, and furthermore migrated toward osteopontin and MIP-1α, factors produced by the MM-OC interaction. These results suggest that Vγ9Vδ2 T cells expanded by zoledronic acid and IL-2 are able to migrate to MM bone lesions and preferentially target OCs as well as MM cells, thereby inhibiting both tumor expansion and bone destruction.