Centro Of Ricerca In Medicina Sperimentale Cerms

Sant'Ambrogio di Torino, Italy

Centro Of Ricerca In Medicina Sperimentale Cerms

Sant'Ambrogio di Torino, Italy
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Castella B.,University of Turin | Castella B.,Centro Of Ricerca In Medicina Sperimentale Cerms | Kopecka J.,University of Turin | Sciancalepore P.,University of Turin | And 15 more authors.
Nature Communications | Year: 2017

Vγ39Vδ2 T cells are activated by phosphoantigens, such as isopentenyl pyrophosphate (IPP), which is generated in the mevalonate pathway of antigen-presenting cells. IPP is released in the extracellular microenvironment via unknown mechanisms. Here we show that the ATP-binding cassette transporter A1 (ABCA1) mediates extracellular IPP release from dendritic cells (DC) in cooperation with apolipoprotein A-I (apoA-I) and butyrophilin-3A1. IPP concentrations in the supernatants are sufficient to induce Vγ39Vδ2 T cell proliferation after DC mevalonate pathway inhibition with zoledronic acid (ZA). ZA treatment increases ABCA1 and apoA-I expression via IPP-dependent LXRα nuclear translocation and PI3K/Akt/mTOR pathway inhibition. These results close the mechanistic gap in our understanding of extracellular IPP release from DC and provide a framework to fine-tune Vγ39Vδ2 T cell activation via mevalonate and PI3K/Akt/mTOR pathway modulation. © The Author(s) 2017.

Foglietta M.,University of Turin | Foglietta M.,Centro Of Ricerca In Medicina Sperimentale Cerms | Castella B.,University of Turin | Castella B.,Centro Of Ricerca In Medicina Sperimentale Cerms | And 13 more authors.
Haematologica | Year: 2014

Conflicting data have been reported about the frequency and function of regulatory T cells in multiple myeloma. Most studies have investigated peripheral blood rather than bone marrow Tregs and side-by-side comparisons with bone marrow from healthy donors have still not been made. In this study, we show that regulatory T-cells total count, subset distribution, and expression of chemokine receptors are similar in the bone marrow of myeloma patients and healthy donors. Regulatory T cells are not recruited by myeloma cells in the bone marrow and their counts are unaffected by the tumor burden and the disease status. The diversity of T-cell receptor repertoire is highly preserved ensuring broad reactivity and effective suppressor function. Our results indicate that regulatory T cells may not be the main players of immunological tolerance to myeloma cells under base-line conditions, but their fully preserved immune competence may promote their inadvertent activation and blunt T-cell driven antimyeloma immune interventions even after myeloma cells have successfully been cleared by chemotherapy. © 2014 Ferrata Storti Foundation.

Piazza R.,University of Milan Bicocca | Valletta S.,University of Milan Bicocca | Winkelmann N.,Salisbury District Hospital | Winkelmann N.,Universitatsklinikum Jena | And 32 more authors.
Nature Genetics | Year: 2013

Atypical chronic myeloid leukemia (aCML) shares clinical and laboratory features with CML, but it lacks the BCR-ABL1 fusion. We performed exome sequencing of eight aCMLs and identified somatic alterations of SETBP1 (encoding a p.Gly870Ser alteration) in two cases. Targeted resequencing of 70 aCMLs, 574 diverse hematological malignancies and 344 cancer cell lines identified SETBP1 mutations in 24 cases, including 17 of 70 aCMLs (24.3%; 95% confidence interval (CI) = 16-35%). Most mutations (92%) were located between codons 858 and 871 and were identical to changes seen in individuals with Schinzel-Giedion syndrome. Individuals with mutations had higher white blood cell counts (P = 0.008) and worse prognosis (P = 0.01). The p.Gly870Ser alteration abrogated a site for ubiquitination, and cells exogenously expressing this mutant exhibited higher amounts of SETBP1 and SET protein, lower PP2A activity and higher proliferation rates relative to those expressing the wild-type protein. In summary, mutated SETBP1 represents a newly discovered oncogene present in aCML and closely related diseases. © 2013 Nature America, Inc. All rights reserved.

Castella B.,Centro Of Ricerca In Medicina Sperimentale Cerms | Castella B.,University of Turin | Foglietta M.,Centro Of Ricerca In Medicina Sperimentale Cerms | Foglietta M.,University of Turin | And 18 more authors.
OncoImmunology | Year: 2015

Vγ9Vδ2 T cells have a natural inclination to recognize malignant B cells in vitro via receptors for stress-induced self-ligands and TCR-dependent recognition of phosphoantigens (pAgs) generated in the mevalonate (Mev) pathway. This inclination is continuously challenged in vivo by 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. © 2015 The Author(s). Published with license by Taylor & Francis Group, LLC.

Coscia M.,Divisione Of Ematologia Delluniversitadi Turin | Coscia M.,Centro Of Ricerca In Medicina Sperimentale Cerms | Vitale C.,Divisione Of Ematologia Delluniversitadi Turin | Vitale C.,Centro Of Ricerca In Medicina Sperimentale Cerms | And 19 more authors.
Blood | Year: 2012

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-tofirst treatment. Accordingly, the time-tofirst 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 dysfunctional Vγ9Vδ2 T cells. © 2012 by The American Society of Hematology.

Riganti C.,University of Turin | Massaia M.,University of Turin | Massaia M.,Centro Of Ricerca In Medicina Sperimentale Cerms
OncoImmunology | Year: 2013

The mevalonate pathway is an attractive target for cancer therapy not only to override multidrug resistance but also to promote the immunogenic demise of malignant cells. Recent data indicate that aminobisphosphonates are superior to statins for the pharmacological manipulation of the mevalonate pathway, since they exert therapeutically relevant effects on both cancer cells and the immune system. ©2013 Landes Bioscience.

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