The clinical course of chronic lymphocytic leukemia (CLL) depends on the intrinsic tumor cell features but also on the interactions between tumor cells, local microenvironment and host immunity. The interplay between CLL cells and conventional αβ T cells has already been investigated in details, whereas very little is known about the role of Vgamma9Vdelta2 T cells. These cells have intrinsic antitumor properties which can be further enhanced by stimulation with aminobisphosphonates such as zoledronic acid (ZA) via monocytes or other antigen-presenting cells. ZA targets the mevalonate (Mev) pathway and induces the intracellular accumulation and release of intermediate metabolites, like isopentenyl pyrophosphate (IPP), which are very similar to the natural ligands of Vgamma9Vdelta2 T cells.
In this study we have performed a phenotypic and functional analysis of Vgamma9Vdelta2 T cells in 93 untreated CLL patients and correlated the results with intrinsic CLL cell features and clinical outcome. Stimulation of peripheral blood mononuclear cells with ZA induced Vgamma9Vdelta2 T cell proliferation in 47/93 patients (responders, R), but not in 46/93 patients (non-responders, NR). Vgamma9Vdelta2 T-cell subset distribution of R CLL was similar to healthy donors, whereas effector memory (EM) and terminally differentiated effector memory (TEMRA) cells predominated in NR CLL. A significant association was found between the R/NR status of Vgamma9Vdelta2 T cells and the mutational status of the tumor IGHV genes: 77% of R patients were M, whereas 70% of UM patients were NR. To test the hypothesis that this difference reflected a different activity of the Mev pathway in M and UM CLL cells, we performed a bioinformatic elaboration of data obtained from gene expression profiling of CLL cells and a biochemical quantification of the Mev pathway in CLL cells including the intermediate metabolites farnesyl pyrophosphate (FPP) and IPP, and the final product cholesterol. The Mev pathway was significantly more active in UM than in M CLL cells, suggesting that the IPP overproduction by UM CLL cells is responsible for a chronic stimulation of Vgamma9Vdelta2 T cells leading to their differentiation into EM and TEMRA cells. This biochemical-driven immunoediting process has clinical implications. After a median follow-up of 46 months from diagnosis, univariate analysis identified R status as a predictor of reduced TFT (NR: 59 months vs R: not reached; p=0.01). The R/NR status also allows to further identify two subsets in UM CLL patients (R-UM and NR-UM) with significantly different TFT (NR-UM: 32 months vs R-UM: not reached; p=0.02). In multivariate analysis, Binet stage (P=0.027), IGHV mutational status (p=0.016), R/NR status (p=0.007), high and low-risk cytogenetic abnormalities (p<0.001) and lymphocytosis at the time of diagnosis (p<0.001) were independent TFT predictors.
In conclusion, we have identified a novel TFT predictor based on a putative interaction between the Mev pathway of CLL cells and Vgamma9Vdelta2 T cells. These results further strengthen the importance of tumor-host immune interactions in CLL evolution.
Boccadoro:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Massaia:Novartis: Honoraria, Research Funding.
Asterisk with author names denotes non-ASH members.