Dysfunctional Vγ9Vδ2 T cells are negative prognosticators and markers of dysregulated mevalonate pathway activity in chronic lymphocytic leukemia cells

The role of Vγ9Vδ2 T cells in chronic lymphocytic leukemia (CLL) is unexplored although these cells have a natural inclination to react against B-cell malignancies. Proliferation induced by zoledronic acid was used as a surrogate of γδ T-cell receptor (TCR)-dependent stimulation to functionally interrogate Vγ9Vδ2 T cells in 106 untreated CLL patients. This assay permitted the identification of responder (R) and low-responder (LR) patients. The LR status was associated to higher baseline counts of Vγ9Vδ2 T cells and to the expansion of the effector memory (EM) and terminally differentiated effector memory (TEMRA) subsets. The tumor immunoglobulin heavy chain variable region was more frequently unmutated (UM) in CLL cells of LR patients, and the mevalonate (Mev) pathway, which generates Vγ9Vδ2 TCR ligands, was more active in UM CLL cells. In addition, higher numbers of circulating regulatory T cells were detected in LR patients. In multivariate analysis the LR condition was an independent predictor of shorter time to first treatment (TTFT). Accordingly, the TTFT was significantly shorter in patients with higher baseline numbers of total Vγ9Vδ2 T cells and EM+TEMRA subpopulations. These results unveil a clinically relevant in vivo relationship between Mev pathway activity of CLL cells and dysfunctional Vγ9Vδ2 T cells.