title: Activated T cells sustain myeloid-derived suppressor cell-mediated immune suppression.
abstract: The expansion of myeloid derived suppressor cells (MDSCs), a suppressive population able to hamper the immune response against cancer, correlates with tumor progression and overall survival in several cancer types. We have previously shown that MDSCs can be induced in vitro from precursors present in the bone marrow and observed that these cells are able to actively proliferate in the presence of activated T cells, whose activation level is critical to drive the suppressive activity of MDSCs. Here we investigated at molecular level the mechanisms involved in the interplay between MDSCs and activated T cells. We found that activated T cells secrete IL-10 following interaction with MDSCs which, in turn, activates STAT3 phosphorylation on MDSCs then leading to B7-H1 expression. We also demonstrated that B7-H1+ MDSCs are responsible for immune suppression through a mechanism involving ARG-1 and IDO expression. Finally, we show that the expression of ligands B7-H1 and MHC class II both on in vitro-induced MDSCs and on MDSCs in the tumor microenvironment of cancer patients is paralleled by an increased expression of their respective receptors PD-1 and LAG-3 on T cells, two inhibitory molecules associated with T cell dysfunction. These findings highlight key molecules and interactions responsible for the extensive cross-talk between MDSCs and activated T cells that are at the basis of immune suppression.
authors.affiliation: Oncology and Immunology Section, Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Pinton
authors.affiliation: Oncology and Immunology Section, Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy.
authors.forename: Samantha
authors.initials: S
authors.lastname: Solito
authors.affiliation: Oncology and Immunology Section, Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy.
authors.forename: Vera
authors.initials: V
authors.lastname: Damuzzo
authors.affiliation: Clinic of Pediatric Hemato-Oncology, Department of Women's and Children's Health, University of Padova, Padova, Italy.
authors.forename: Samuela
authors.initials: S
authors.lastname: Francescato
authors.affiliation: Surgery Section, Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy.
authors.forename: Assunta
authors.initials: A
authors.lastname: Pozzuoli
authors.affiliation: Surgery Section, Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Berizzi
authors.affiliation: Surgery Section, Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy.|Surgical Oncology Unit, Veneto Institute of Oncology - IOV-IRCSS, Padua, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Mocellin
authors.affiliation: Surgery Section, Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy.|Surgical Oncology Unit, Veneto Institute of Oncology - IOV-IRCSS, Padua, Italy.
authors.forename: Carlo Riccardo
authors.initials: CR
authors.lastname: Rossi
authors.affiliation: University of Verona, Department of Pathology and Diagnostic, Section of Immunology, Verona, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Bronte
authors.affiliation: Oncology and Immunology Section, Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy.|Veneto Institute of Oncology - IOV-IRCSS, Padua, Italy.
authors.forename: Susanna
authors.initials: S
authors.lastname: Mandruzzato
mesh_terms: D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D001119:Arginase / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D060890:B7-H1 Antigen / Q000276:immunology / Q000378:metabolism; D015153:Blotting, Western; D002450:Cell Communication / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D015870:Gene Expression / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics / Q000276:immunology*; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D022423:Myeloid Cells / Q000276:immunology* / Q000378:metabolism; D010766:Phosphorylation / Q000276:immunology; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D059016:Tumor Microenvironment / Q000235:genetics / Q000276:immunology; D000093322:Lymphocyte Activation Gene 3 Protein
chemical_list: D015703:Antigens, CD; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D000949:Histocompatibility Antigens Class II; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D061026:Programmed Cell Death 1 Receptor; D050796:STAT3 Transcription Factor; D016753:Interleukin-10; C574619:ARG1 protein, human; D001119:Arginase; D000093322:Lymphocyte Activation Gene 3 Protein; C000720326:Lag3 protein, human
keywords: Immune response; Immunity; Immunology and Microbiology Section; MDSC; immune regulatory pathways; immune suppression; tolerance; tumor microenvironment