title: Anergic bone marrow Vγ9Vδ2 T cells as early and long-lasting markers of PD-1-targetable microenvironment-induced immune suppression in human myeloma.
abstract: Vγ9Vδ2 T cells have a natural inclination to recognize malignant B cellsin vitrovia receptors for stress-induced self-ligands and TCR-dependent recognition of phosphoantigens (pAgs) generated in the mevalonate (Mev) pathway. This inclination is continuously challengedin vivoby the immune suppression operated by tumor cells. Multiple myeloma (MM) is a prototypic B-cell malignancy in which myeloma cells subvert the local microenvironment to reshape antitumor immune responses. In this study, we have investigated the immune competence of bone marrow (BM) Vγ9Vδ2 T cells in a large series of MM patients. We have found that the BM microenvironment significantly hampers the pAg-reactivity of BM Vγ9Vδ2 T cells, which become largely PD-1+and are surrounded by PD-L1+myeloma cells and increased numbers of PD-L1+myeloid-derived suppressor cells (MDSC). Vγ9Vδ2 T-cell dysfunction is an early event that can be already detected in individuals with monoclonal gammopathy of undetermined significance (MGUS) and not fully reverted even when MM patients achieve clinical remission. Anti-PD-1 treatment increases the cytotoxic potential of Vγ9Vδ2 T cells by almost 5-fold after pAg stimulation, and appears to be a promising strategy for effective immune interventions in MM.
authors.affiliation: Laboratorio di Ematologia Oncologica; Centro di Ricerca in Medicina Sperimentale (CeRMS); Torino, Italy ; Dipartimento di Biotecnologie Molecolari e Scienze per la Salute; Università degli Studi di Torino ; Torino, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Castella
authors.affiliation: Laboratorio di Ematologia Oncologica; Centro di Ricerca in Medicina Sperimentale (CeRMS); Torino, Italy ; Dipartimento di Biotecnologie Molecolari e Scienze per la Salute; Università degli Studi di Torino ; Torino, Italy.
authors.forename: Myriam
authors.initials: M
authors.lastname: Foglietta
authors.affiliation: Laboratorio di Ematologia Oncologica; Centro di Ricerca in Medicina Sperimentale (CeRMS); Torino, Italy ; S.C. Ematologia I; Università degli Studi di Torino ; Torino, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Sciancalepore
authors.affiliation: Laboratorio di Ematologia Oncologica; Centro di Ricerca in Medicina Sperimentale (CeRMS); Torino, Italy ; Dipartimento di Biotecnologie Molecolari e Scienze per la Salute; Università degli Studi di Torino ; Torino, Italy.
authors.forename: Micol
authors.initials: M
authors.lastname: Rigoni
authors.affiliation: Laboratorio di Ematologia Oncologica; Centro di Ricerca in Medicina Sperimentale (CeRMS); Torino, Italy ; Dipartimento di Biotecnologie Molecolari e Scienze per la Salute; Università degli Studi di Torino ; Torino, Italy ; S.C. Ematologia I; Università degli Studi di Torino ; Torino, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Coscia
authors.affiliation: Laboratorio di Ematologia Oncologica; Centro di Ricerca in Medicina Sperimentale (CeRMS); Torino, Italy ; Dipartimento di Biotecnologie Molecolari e Scienze per la Salute; Università degli Studi di Torino ; Torino, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Griggio
authors.affiliation: Laboratorio di Ematologia Oncologica; Centro di Ricerca in Medicina Sperimentale (CeRMS); Torino, Italy ; S.C. Ematologia I; Università degli Studi di Torino ; Torino, Italy.
authors.forename: Candida
authors.initials: C
authors.lastname: Vitale
authors.affiliation: Divisione di Ortopedia, Azienda Ospedaliera-Universitaria Città della Salute e della Scienza di Torino ; Torino, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Ferracini
authors.affiliation: S.C. Ematologia I; Università degli Studi di Torino ; Torino, Italy.
authors.forename: Elona
authors.initials: E
authors.lastname: Saraci
authors.affiliation: S.C. Ematologia I; Università degli Studi di Torino ; Torino, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Omedé
authors.affiliation: Dipartimento di Oncologia; Università degli Studi di Torino ; Torino, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Riganti
authors.affiliation: S.C. Ematologia I; Università degli Studi di Torino ; Torino, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Palumbo
authors.affiliation: S.C. Ematologia I; Università degli Studi di Torino ; Torino, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Boccadoro
authors.affiliation: Laboratorio di Ematologia Oncologica; Centro di Ricerca in Medicina Sperimentale (CeRMS); Torino, Italy ; Dipartimento di Biotecnologie Molecolari e Scienze per la Salute; Università degli Studi di Torino ; Torino, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Massaia
keywords: MDSC; PD-1/PDL-1 pathway; Vγ9Vδ2 T cells; multiple myeloma