title: Dysfunctional Vγ9Vδ2 T cells are negative prognosticators and markers of dysregulated mevalonate pathway activity in chronic lymphocytic leukemia cells.
abstract: 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 TCR-dependent stimulation to functionally interrogate Vγ9Vδ2 T cells in 106 untreated CLL patients. This assay permitted the identification of responder and low-responder (LR) patients. The LR status was associated with greater baseline counts of Vγ9Vδ2 T cells and to the expansion of the effector memory and terminally differentiated effector memory subsets. The tumor immunoglobulin heavy chain variable region was more frequently unmutated in CLL cells of LR patients, and the mevalonate pathway, which generates Vγ9Vδ2 TCR ligands, was more active in unmutated CLL cells. In addition, greater 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. Accordingly, the time-to-first treatment was significantly shorter in patients with greater baseline numbers of total Vγ9Vδ2 T cells and effector memory and terminally differentiated effector memory subpopulations. These results unveil a clinically relevant in vivo relationship between the mevalonate pathway activity of CLL cells and dys-functional Vγ9Vδ2 T cells.
authors.affiliation: Divisione di Ematologia dell'Università di Torino, Azienda Ospedaliera Città della Salute e della Scienza di Torino, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Coscia
authors.forename: Candida
authors.initials: C
authors.lastname: Vitale
authors.forename: Silvia
authors.initials: S
authors.lastname: Peola
authors.forename: Myriam
authors.initials: M
authors.lastname: Foglietta
authors.forename: Micol
authors.initials: M
authors.lastname: Rigoni
authors.forename: Valentina
authors.initials: V
authors.lastname: Griggio
authors.forename: Barbara
authors.initials: B
authors.lastname: Castella
authors.forename: Daniela
authors.initials: D
authors.lastname: Angelini
authors.forename: Sabina
authors.initials: S
authors.lastname: Chiaretti
authors.forename: Chiara
authors.initials: C
authors.lastname: Riganti
authors.forename: Anna
authors.initials: A
authors.lastname: Guarini
authors.forename: Daniela
authors.initials: D
authors.lastname: Drandi
authors.forename: Marco
authors.initials: M
authors.lastname: Ladetto
authors.forename: Amalia
authors.initials: A
authors.lastname: Bosia
authors.forename: Robin
authors.initials: R
authors.lastname: Foà
authors.forename: Luca
authors.initials: L
authors.lastname: Battistini
authors.forename: Mario
authors.initials: M
authors.lastname: Boccadoro
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Fournié
authors.forename: Massimo
authors.initials: M
authors.lastname: Massaia
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D050071:Bone Density Conservation Agents / Q000494:pharmacology; D016022:Case-Control Studies; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D004164:Diphosphonates / Q000494:pharmacology; D005260:Female; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D051228:Geranyltranstransferase / Q000037:antagonists & inhibitors; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007156:Immunologic Memory / Q000276:immunology*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology* / Q000378:metabolism / Q000401:mortality; D008213:Lymphocyte Activation / Q000276:immunology*; D008297:Male; D008798:Mevalonic Acid / Q000378:metabolism*; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D015996:Survival Rate; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D000077211:Zoledronic Acid
chemical_list: D014408:Biomarkers, Tumor; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D012333:RNA, Messenger; D016692:Receptors, Antigen, T-Cell, gamma-delta; D000077211:Zoledronic Acid; D051228:Geranyltranstransferase; D008798:Mevalonic Acid