Vincenzo Bronte

Venetian Institute of Molecular Medicine, Padua, Veneto, Italy

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Publications (157)1183.63 Total impact

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    ABSTRACT: Myeloid-derived suppressor cells (MDSC) are a naturally occurring immune regulatory population associated with inhibition of ongoing inflammatory responses. In vitro generation of MDSC from bone marrow have been shown to enhance survival in an acute model of lethal graft-versus-host disease (GvHD). However, donor MDSC infusion only partially ameliorates GvHD lethality. In order to improve the potential therapeutic benefit and ultimately survival outcomes we set out to investigate the fate of MDSC after transfer in the setting of acute GvHD (aGvHD). MDSC transferred to lethally irradiated recipients of allogeneic donor hematopoietic grafts are exposed to an intense inflammatory environment associated with aGvHD, which we now show directly undermines their suppressive capacity. Under conditioning regimen and GvHD inflammatory settings, MDSC rapidly lose suppressor function and their potential to inhibit GvHD lethality, which is associated with their induced conversion towards a mature inflammasome-activated state. We find even brief in vitro exposure to inflammasome-activating mediators negates the suppressive potential of cultured murine and human-derived MDSCs. Consistent with a role for the inflammasome, donor MDSC deficient in the adaptor ASC (Apoptosis-associated speck-like protein containing a CARD), that assembles inflammasome complexes, conferred improved survival of mice developing GvHD compared to wild-type donor MDSC. These data suggest the use of MDSC as a therapeutic approach for preventing GvHD and other systemic inflammatory conditions will be more effective when combined with approaches limiting in vivo MDSC inflammasome activation empowering MDSCs to maintain their suppressive potential. Copyright © 2015 American Society of Hematology.
    Blood 08/2015; DOI:10.1182/blood-2015-03-634691 · 10.43 Impact Factor
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    ABSTRACT: The incomplete clinical efficacy of anti-tumor immunotherapy can depend on the presence of an immunosuppressive environment in the host that supports tumor progression. Tumor-derived cytokines and growth factors induce an altered hematopoiesis that modifies the myeloid cell differentiation process, promoting proliferation and expansion of cells with immunosuppressive skills, namely myeloid derived suppressor cells (MDSCs). MDSCs promote tumor growth not only by shaping immune responses towards tumor tolerance, but also by supporting several processes necessary for the neoplastic progression such as tumor angiogenesis, cancer stemness, and metastasis dissemination. Thus, MDSC targeting represents a promising tool to eliminate host immune dysfunctions and increase the efficacy of immune-based cancer therapies. Copyright © 2015. Published by Elsevier B.V.
    Biochimica et Biophysica Acta 08/2015; DOI:10.1016/j.bbcan.2015.08.001 · 4.66 Impact Factor
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    ABSTRACT: Myeloid derived suppressor cells (MDSC) contribute significantly to the malignant characters conferred by hypoxic tumor microenvironments. However, selective biomarkers of MDSC function in this critical setting have not been defined. Here we report that miR-210 expression is elevated by HIF-1α in MDSC localized to tumors, compared to splenic MDSC from tumor-bearing mice. In tumor MDSC, we determined that HIF-1α was bound directly to a transcriptionally active hypoxia-response element in the miR-210 proximal promoter. miR-210 overexpression was sufficient to enhance MDSC-mediated T cell suppression under normoxic conditions, while targeting hypoxia-induced miR-210 was sufficient to decrease MDSC function against T cells. Mechanistic investigations revealed that miR-210 modulated MDSC function by increasing arginase activity and NO production, without affecting ROS, IL-6 or IL-10 production or expression of PD-L1. In splenic MDSC, miR-210 regulated Arg1, Cxcl12 and IL-16 at the levels of both mRNA and protein, the reversal of which under normoxic conditions decreased T cell suppressive effects and IFN-gamma production. Interestingly, miR-210 overexpression or targeting IL-16 or CXCL12 enhanced the immune suppressive activity of MDSC in vivo resulting in increased tumor growth. Taken together, these results provide a preclinical rationale to explore miR-210 inhibitory oligonucleotides as adjuvants to boost immunotherapeutic responses in cancer patients. Copyright © 2015, American Association for Cancer Research.
    Cancer Research 07/2015; DOI:10.1158/0008-5472.CAN-15-0405 · 9.28 Impact Factor
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    ABSTRACT: The potential predictive role of programmed death-ligand-1 (PD-L1) expression on tumor cells in the context of solid tumor treated with checkpoint inhibitors targeting the PD-1 pathway represents an issue for clinical research. Overall response rate (ORR) was extracted from phase I-III trials investigating nivolumab, pembrolizumab and MPDL3280A for advanced melanoma, non-small cell lung cancer (NSCLC) and genitourinary cancer, and cumulated by adopting a fixed and random-effect model with 95% confidence interval (CI). Interaction test according to tumor PD-L1 was accomplished. A sensitivity analysis according to adopted drug, tumor type, PD-L1 cut-off and treatment line was performed. Twenty trials (1,475 patients) were identified. A significant interaction (p<0.0001) according to tumor PD-L1 expression was found in the overall sample with an ORR of 34.1% (95% CI 27.6-41.3%) in the PD-L1 positive and 19.9% (95% CI 15.4-25.3%) in the PD-L1 negative population. ORR was significantly higher in PD-L1 positive in comparison to PD-L1 negative patients for nivolumab and pembrolizumab, with an absolute difference of 16.4% and 19.5%, respectively. A significant difference in activity of 22.8% and 8.7% according to PD-L1 was found for melanoma and NSCLC, respectively, with no significant difference for genitourinary cancer. Overall, the three antibodies provide a significant differential effect in terms of activity according to PD-L1 expression on tumor cells. The predictive value of PD-L1 on tumor cells seems to be more robust for anti-PD-1 antibody (nivolumab and pembrolizumab), and in the context of advanced melanoma and NSCLC.
    PLoS ONE 06/2015; 10(6):e0130142. DOI:10.1371/journal.pone.0130142 · 3.23 Impact Factor
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    ABSTRACT: Tissue effector cells of the monocyte lineage can differentiate into different cell types with specific cell function depending on their environment. The phenotype, developmental requirements, and functional mechanisms of immune protective macrophages that mediate the induction of transplantation tolerance remain elusive. Here, we demonstrate that costimulatory blockade favored accumulation of DC-SIGN-expressing macrophages that inhibited CD8(+) T cell immunity and promoted CD4(+)Foxp3(+) Treg cell expansion in numbers. Mechanistically, that simultaneous DC-SIGN engagement by fucosylated ligands and TLR4 signaling was required for production of immunoregulatory IL-10 associated with prolonged allograft survival. Deletion of DC-SIGN-expressing macrophages in vivo, interfering with their CSF1-dependent development, or preventing the DC-SIGN signaling pathway abrogated tolerance. Together, the results provide new insights into the tolerogenic effects of costimulatory blockade and identify DC-SIGN(+) suppressive macrophages as crucial mediators of immunological tolerance with the concomitant therapeutic implications in the clinic. Copyright © 2015 Elsevier Inc. All rights reserved.
    Immunity 06/2015; 42(6). DOI:10.1016/j.immuni.2015.05.009 · 19.75 Impact Factor
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    Jordi Ochando · Patricia Conde · Vincenzo Bronte
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    ABSTRACT: Myeloid-derived suppressor cells (MDSC) are cells of myeloid origin with enhanced suppressive function. They are negative regulators of the immune responses and comprise a heterogeneous mixture of immunosuppressive cells of monocytic (M-MDSC) and granulocytic (G-MDSC) origin. A more recent nomenclature proposes the term “suppressive monocyte derived cells” (suppressive MCs) to define CSF1/CSF2-dependent mouse suppressor cells that develop from common monocyte progenitors (cMoPs) after birth. Here, we review the literature about monocytic-derived cells with demonstrated suppressor function in vitro and in vivo within the context of solid organ transplantation.
    06/2015; 2(2). DOI:10.1007/s40472-015-0054-9
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    ABSTRACT: In the Sp6 mouse plasmacytoma model, a whole cell vaccination with Sp6 cells expressing de novo B7-1 (Sp6/B7) induced an anatomically localized and cytotoxic T cells (CTLs)-mediated protection against wild type (WT) Sp6. Both WT Sp6 and Sp6/B7 showed a down-regulated expression of MHC H-2 L(d) . Increase of H-2 L(d) expression by cDNA transfection (Sp6/B7/L(d) ) raised tumour immune protection and shifted most CTL responses towards H-2 L(d) -restricted antigenic epitopes. The tumour-protective responses were not specific for the H-2 L(d) -restricted immunodominant AH1 epitope of the gp70 common mouse tumour antigen, although WT Sp6 and transfectants were able to present it to specific T cells in vitro. Gp70 transcripts, absent in secondary lymphoid organs of naïve mice, were detected in immunised mice as well as in splenocytes from naïve mice incubated in vitro with supernatants of CTL-lysed Sp6 cell cultures, containing damage associated molecular patterns (DAMPs). It has been shown that Toll like receptors (TLRs) triggering induces gp70 expression. DAMPs released by CTL-mediated killing of Sp6/B7-Sp6/B7/L(d) cells migrated to draining lymph nodes during immunisation may activate gp70 expression and presentation in most resident antigen presenting cells (APCs). The same could also apply for MuMLV virus particles present in Sp6-cytosol, discharged by dying cells and superinfecting APCs. The outcome of such a massive gp70 cross-presentation would likely be tolerogenic for the high affinity AH1-gp70-specific CTLs clones. In this scenario, autologous whole-tumour-cell vaccines rescue tumour-specific immunoprotection by amplification of subdominant tumour antigen responses when those against the immune dominant antigens are lost. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Immunology 05/2015; DOI:10.1111/imm.12477 · 3.74 Impact Factor
  • Ainhoa Arina · Vincenzo Bronte
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    ABSTRACT: Novel models of autochthonous tumorigenesis and adoptive T cell therapy (ATT) are providing new clues regarding the pro-tumorigenic and immunosuppressive effects of myeloid-derived suppressor cells (MDSC), and their interaction with T cells. New findings are shifting the perception of the main level at which MDSC act, from direct cell-to-cell suppression to others, such as limiting T cell infiltration. Adoptively transferred, high-avidity T cells recognizing peptides with high-affinity for MHC-I eliminated large tumors. However, low-avidity T cells or low-affinity peptides resulted in failure to eradicate tumors. Manipulation of intratumoral myeloid cells improved the outcome of otherwise unsuccessful ATT. Therefore, therapeutic intervention directed at the tumor stroma might be required when using suboptimal T cells for ATT. Copyright © 2015. Published by Elsevier Ltd.
    Current Opinion in Immunology 04/2015; 33. DOI:10.1016/j.coi.2015.02.006 · 7.87 Impact Factor
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    ABSTRACT: Ionizing and nonionizing radiation affect not only directly targeted cells but also surrounding "bystander" cells. The underlying mechanisms and therapeutic role of bystander responses remain incompletely defined. Here we show that photosentizer activation in a single cell triggers apoptosis in bystander cancer cells, which are electrically coupled by gap junction channels and support the propagation of a Ca2+ wave initiated in the irradiated cell. The latter also acts as source of nitric oxide (NO) that diffuses to bystander cells, in which NO levels are further increased by a mechanism compatible with Ca2+-dependent enzymatic production. We detected similar signals in tumors grown in dorsal skinfold chambers applied to live mice. Pharmacological blockade of connexin channels significantly reduced the extent of apoptosis in bystander cells, consistent with a critical role played by intercellular communication, Ca2+ and NO in the bystander effects triggered by photodynamic therapy.
    Oncotarget 03/2015; · 6.63 Impact Factor
  • Vincenzo Bronte · Peter J Murray
    Nature Medicine 02/2015; 21(2):117-9. DOI:10.1038/nm.3794 · 28.05 Impact Factor
  • Vincenzo Bronte · Peter J. Murray
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    ABSTRACT: Recent studies have suggested that manipulating the tumor-associated macrophage phenotype is a valid therapeutic approach in cancer. In turn, these studies have given some insight into the factors that polarize macrophages, thereby suggesting alternative therapeutic avenues.
    Nature Medicine 02/2015; 21(2):29-31. · 28.05 Impact Factor
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    ABSTRACT: Myeloid-derived suppressor cells (MDSCs) have been shown to control self-reactive and anti-graft effector T-cells in autoimmunity and transplantation, but their therapeutic use is limited by their scarce availability in the peripheral blood of tumor-free donors. We isolated and characterized a novel population of myeloid suppressor cells, named fibrocytic MDSC (f-MDSC), which are differentiated from umbilical cord blood (UCB) precursors (Zoso et al., 2014). This MDSC subset promotes regulatory T-cell expansion and induces normoglycemia in a xenogeneic model of type 1 diabetes. Here we describe in details the experimental design and the bioinformatics analyses of the gene expression dataset used to investigate the molecular mechanisms at the base of MDSC tolerogenic and suppressive properties. We also provide an R code to easily access the data and perform the quality controls and basic analyses relevant to this dataset. Raw and pre-processed data are available at Gene Expression Omnibus under accession GSE52376.
    12/2014; 2. DOI:10.1016/j.gdata.2014.10.018
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    ABSTRACT: Nonresolving inflammation expands a heterogeneous population of myeloid suppressor cells capable of inhibiting T cell function. This heterogeneity has confounded the functional dissection of individual myeloid subpopulations and presents an obstacle for antitumor immunity and immunotherapy. Using genetic manipulation of cell death pathways, we found the monocytic suppressor-cell subset, but not the granulocytic subset, requires continuous c-FLIP expression to prevent caspase-8-dependent, RIPK3-independent cell death. Development of the granulocyte subset requires MCL-1-mediated control of the intrinsic mitochondrial death pathway. Monocytic suppressors tolerate the absence of MCL-1 provided cytokines increase expression of the MCL-1-related protein A1. Monocytic suppressors mediate T cell suppression, whereas their granulocytic counterparts lack suppressive function. The loss of the granulocytic subset via conditional MCL-1 deletion did not alter tumor incidence implicating the monocytic compartment as the functionally immunosuppressive subset in vivo. Thus, death pathway modulation defines the development, survival, and function of myeloid suppressor cells. Copyright © 2014 Elsevier Inc. All rights reserved.
    Immunity 12/2014; 41(6). DOI:10.1016/j.immuni.2014.10.020 · 19.75 Impact Factor
  • Vincenzo Bronte
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    ABSTRACT: Immunotherapy is revolutionizing the treatment of cancer patients, but the molecular basis for tumor immunogenicity is unclear. In this issue of Immunity, Deng et al. (2014) and Woo et al. (2014) provide evidence suggesting that dendritic cells detect DNA from tumor cells via the STING-mediated, cytosolic DNA sensing pathway. Copyright © 2014 Elsevier Inc. All rights reserved.
    Immunity 11/2014; 41(5):679-681. DOI:10.1016/j.immuni.2014.11.004 · 19.75 Impact Factor
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    ABSTRACT: Study of myeloid cells endowed with suppressive activity is an active field of research which has particular importance in cancer, in view of the negative regulatory capacity of these cells to the host's immune response. The expansion of these cells, called myeloid-derived suppressor cells (MDSCs), has been documented in many models of tumor-bearing mice and in patients with tumors of various origin, and their presence is associated with disease progression and reduced survival. For this reason, monitoring this type of cell expansion is of clinical importance, and flow cytometry is the technique of choice for their identification. Over the years, it has been demonstrated that MDSCs comprise a group of immature myeloid cells belonging both to monocytic and granulocytic lineages, with several stages of differentiation; their occurrence depends on tumor-derived soluble factors, which guide their expansion and determine their block of differentiation. Because of their heterogeneous composition, accurate phenotyping of these cells requires a multicolor approach, so that the expansion of all MDSC subsets can be appreciated.This review article focuses on identifying MDSCs and discusses problems associated with phenotyping circulating and tumor-associated MDSCs in humans and in mouse models. This article is protected by copyright. All rights reserved.
    Cytometry Part B Clinical Cytometry 11/2014; 88(2). DOI:10.1002/cytob.21206 · 2.28 Impact Factor
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    ABSTRACT: By restraining T-cell activation and promoting Treg-cell expansion, myeloid-derived suppressor cells (MDSCs) and tolerogenic dendritic cells (tDCs) can control self-reactive and anti-graft effector T cells in autoimmunity and transplantation. Their therapeutic use and characterization, however, is limited by their scarce availability in the peripheral blood of tumor-free donors. In the present study, we describe and characterize a novel population of human myeloid suppressor cells, named fibrocytic MDSC (f-MDSCs), which are differentiated from umbilical cord blood (UCB) precursors by 4-day culture with FDA-approved cytokines (rh-GM-CSF and rh-G-CSF). This MDSC subset, characterized by the expression of MDSC-, DC-, and fibrocyte-associated markers, promotes Treg-cell expansion and induces normoglycemia in a xenogeneic mouse model of Type 1 diabetes (T1D). In order to exert their pro-tolerogenic function, fibrocytic MDSCs require direct contact with activated T cells, which leads to the production and secretion of IDO. This new myeloid subset may have an important role in the in vitro and in vivo production of Treg cells for the treatment of autoimmune diseases, and in either the prevention or control of allograft rejection.This article is protected by copyright. All rights reserved
    European Journal of Immunology 11/2014; 44(11). DOI:10.1002/eji.201444522 · 4.52 Impact Factor
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    ABSTRACT: We analyzed the interactions between primary cells from pancreatic ductal adenocarcinoma (PDAC) and polymeric scaffolds to develop 3D cancer models useful for mimicking the biology of this tumor. Three scaffold types based on two biocompatible polymeric formulations, such as poly(vinyl alcohol)/gelatin (PVA/G) mixture and poly(ethylene oxide terephthalate)/poly(butylene terephthalate) (PEOT/PBT) copolymer, were obtained via different techniques, namely, emulsion and freeze-drying, compression molding followed by salt leaching, and electrospinning. In this way, primary PDAC cells interfaced with different pore topographies, such as sponge-like pores of different shape and size or nanofiber interspaces. The aim of this study was to investigate the influence played by the scaffold architecture over cancerous cell growth and function. In all scaffolds, primary PDAC cells showed good viability and synthesized tumor-specific metalloproteinases (MMPs) such as MMP-2, and MMP-9. However, only sponge-like pores, obtained via emulsion-based and salt leaching-based techniques allowed for an organized cellular aggregation very similar to the native PDAC morphological structure. Differently, these cell clusters were not observed on PEOT/PBT electrospun scaffolds. MMP-2 and MMP-9, as active enzymes, resulted to be increased in PVA/G and PEOT/PBT sponges, respectively. These findings suggested that spongy scaffolds supported the generation of pancreatic tumor models with enhanced aggressiveness. In conclusion, primary PDAC cells showed diverse behaviors while interacting with different scaffold types that can be potentially exploited to create stage-specific pancreatic cancer models likely to provide new knowledge on the modulation and drug susceptibility of MMPs.
    08/2014; 4(1). DOI:10.4161/21592527.2014.955386
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    ABSTRACT: Trehalose-6,6-dimycolate (TDM), the mycobacterial cord factor, and its synthetic analog Trehalose-6,6-dibehenate (TDB) bind to the C-type lectin receptors macrophage-inducible C-type lectin (Mincle) and Mcl to activate macrophages. Genetically, the transcriptional response to TDB/TDM has been defined to require FcRγ-Syk-Card9 signaling. However, TDB/TDM-triggered kinase activation has not been studied well, and it is largely unknown which transcriptional regulators bring about inflammatory gene expression. In this article, we report that TDB/TDM caused only weak Syk-phosphorylation in resting macrophages, consistent with low basal Mincle expression. However, LPS-priming caused MYD88-dependent upregulation of Mincle, resulting in enhanced TDB/TDM-induced kinase activation and more rapid inflammatory gene expression. TLR-induced Mincle expression partially circumvented the requirement for Mcl in the response to TDB/TDM. To dissect transcriptional responses to TDB/TDM, we mined microarray data and identified early growth response (Egr) family transcription factors as direct Mincle target genes, whereas upregulation of Cebpb and Hif1a required new protein synthesis. Macrophages and dendritic cells lacking C/EBPβ showed nearly complete abrogation of TDB/TDM responsiveness, but also failed to upregulate Mincle. Retroviral rescue of Mincle expression in Cebpb-deficient cells restored induction of Egr1, but not of G-CSF. This pattern of C/EBPβ dependence was also observed after stimulation with the Dectin-1 ligand Curdlan. Inducible expression of hypoxia-inducible factor 1α (HIF1α) also required C/EBPβ. In turn, HIF1α was not required for Mincle expression, kinase activation, and Egr1 or Csf3 expression, but critically contributed to NO production. Taken together, we identify C/EBPβ as central hub in Mincle expression and inflammatory gene induction, whereas HIF1α controls Nos2 expression. C/EBPβ also connects TLR signals to cord factor responsiveness through MYD88-dependent upregulation of Mincle.
    The Journal of Immunology 08/2014; 193(7). DOI:10.4049/jimmunol.1301593 · 5.36 Impact Factor
  • Vincenzo Bronte
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    ABSTRACT: Immunology and Cell Biology focuses on the general functioning of the immune system in its broadest sense, with a particular emphasis on its cell biology. Areas that are covered include but are not limited to: Cellular immunology, Innate and adaptive immunity, Immune responses to pathogens,Tumour immunology,Immunopathology, Immunotherapy, Immunogenetics, Immunological studies in humans and model organisms (including mouse, rat, Drosophila etc)
    Immunology and Cell Biology 08/2014; 92(8). DOI:10.1038/icb.2014.67 · 4.21 Impact Factor
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    ABSTRACT: The dynamic interplay between cancer and host immune system often affects the process of myelopoiesis. As a consequence, tumor-derived factors sustain the accumulation and functional differentiation of myeloid cells, including myeloid-derived suppressor cells (MDSCs), which can interfere with T cell-mediated responses. Since both the phenotype and mechanisms of action of MDSCs appear to be tumor-dependent, it is important not only to determine the presence of all MDSC subsets in each cancer patient, but also which MDSC subsets have clinical relevance in each tumor environment. In this review, we describe the differences between MDSC populations expanded within different tumor contexts and evaluate the prognostic significance of MDSC expansion in peripheral blood and within tumor masses of neoplastic patients.
    Annals of the New York Academy of Sciences 06/2014; 1319(1):47-65. DOI:10.1111/nyas.12469 · 4.31 Impact Factor

Publication Stats

11k Citations
1,183.63 Total Impact Points

Institutions

  • 2010–2015
    • Venetian Institute of Molecular Medicine
      Padua, Veneto, Italy
    • University of Verona
      • • Department of Pathology
      • • Department of Pathology and Diagnostics
      • • Section of Immunology
      Verona, Veneto, Italy
  • 2012
    • University of Milan
      • Department of Medical Biotechnology and Translational Medicine
      Milano, Lombardy, Italy
  • 1999–2012
    • NCI-Frederick
      Фредерик, Maryland, United States
  • 2011
    • Center of Molecular Immunology
      La Habana, Ciudad de La Habana, Cuba
    • Istituto Nazionale Tumori "Fondazione Pascale"
      Napoli, Campania, Italy
  • 2009–2011
    • Istituto di Cura e Cura a Carattere Scientifico Basilicata
      Rionero in Vulture, Basilicate, Italy
  • 2006–2010
    • Istituto Oncologico Veneto
      Padua, Veneto, Italy
  • 1989–2010
    • University of Padova
      • • Dipartimento di Scienze Mediche e Chirurgiche
      • • Department of Biomedical Sciences - DSB
      Padua, Veneto, Italy
  • 2007
    • New York State
      New York City, New York, United States
  • 2004
    • University of Bonn
      Bonn, North Rhine-Westphalia, Germany
  • 2002–2004
    • University-Hospital of Padova
      Padua, Veneto, Italy
  • 2000
    • University of Bologna
      Bolonia, Emilia-Romagna, Italy
  • 1995–1999
    • National Institutes of Health
      • • Branch of Surgery
      • • Branch of Experimental Immunology
      Maryland, United States
  • 1997
    • National Institute of Allergy and Infectious Diseases
      • Laboratory of Immunoregulation
      Maryland, United States
  • 1995–1996
    • National Cancer Institute (USA)
      • Surgery Branch
      베서스다, Maryland, United States
  • 1992–1995
    • It-Robotics
      Vicenza, Veneto, Italy
  • 1994
    • University of Ferrara
      Ferrare, Emilia-Romagna, Italy