title: Chronic lymphocytic leukemia nurse-like cells express hepatocyte growth factor receptor (c-MET) and indoleamine 2,3-dioxygenase and display features of immunosuppressive type 2 skewed macrophages.
abstract: Hepatocyte growth factor, produced by stromal and follicular dendritic cells, and present at high concentrations in the sera of patients with chronic lymphocytic leukemia, prolongs the survival of leukemic B cells by interacting with their receptor, c-MET. It is, however, unknown whether hepatocyte growth factor influences microenvironmental cells, such as nurse-like cells, which deliver survival signals to the leukemic clone. We evaluated the expression of c-MET on nurse-like cells and monocytes from patients with chronic lymphocytic leukemia and searched for phenotypic/functional features supposed to be influenced by the hepatocyte growth factor/c-MET interaction. c-MET is expressed at high levels on nurse-like cells and at significantly higher levels than normal on monocytes from patients. Moreover, the hepatocyte growth factor/c-MET interaction activates STAT3(TYR705) phosphorylation in nurse-like cells. Indoleamine 2,3-dioxygenase, an enzyme modulating T-cell proliferation and induced on normal monocytes after hepatocyte growth factor treatment, was detected together with interleukin-10 on nurse-like cells, and on freshly-prepared patients' monocytes. Immunohistochemical/immunostaining analyses demonstrated the presence of c-MET(+) and indoleamine 2,3-dioxygenase(+) cells in lymph node biopsies, co-expressed with CD68 and vimentin. Furthermore nurse-like cells and chronic lymphocytic monocytes significantly inhibited T-cell proliferation, prevented by anti-transforming growth factor beta and interleukin-10 antibodies and indoleamine 2,3-dioxygenase inhibitors, and supported CD4(+)CD25(high+)/FOXP3(+) T regulatory cell expansion. We suggest that nurse-like cells display features of immunosuppressive type 2 macrophages: higher hepatocyte growth factor levels, produced by leukemic or other microenvironmental surrounding cells, may cooperate to induce M2 polarization. Hepatocyte growth factor may thus have a dual pathophysiological role: directly through enhancement of survival of the leukemic clone and indirectly by favoring T-cell immunosuppression.
authors.affiliation: Dept. of Experimental Medicine (Di.Me.S), University of Genoa, Genoa, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Giannoni
authors.affiliation: Dept. of Experimental Medicine (Di.Me.S), University of Genoa, Genoa, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Pietra
authors.affiliation: Transfer Gene Laboratory, IRCCS AOU San Martino-IST, Genoa, Italy.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Travaini
authors.affiliation: Dept. of Experimental Medicine (Di.Me.S), University of Genoa, Genoa, Italy.
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Quarto
authors.affiliation: Dept. of Experimental Medicine (Di.Me.S), University of Genoa, Genoa, Italy.
authors.forename: Genti
authors.initials: G
authors.lastname: Shyti
authors.affiliation: Immunology, Dept. of Integrated Oncology Therapies, IRCCS AOU San Martino-IST, Genoa, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Benelli
authors.affiliation: Pathology and Molecular Diagnostic Laboratory, Dept. of Service, IRCCS AOU San Martino-IST, Genoa, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Ottaggio
authors.affiliation: Dept. of Experimental Medicine (Di.Me.S), University of Genoa, Genoa, Italy Excellence Center for Biomedical Research, University of Genoa, Genoa, Italy Immunology, Dept. of Integrated Oncology Therapies, IRCCS AOU San Martino-IST, Genoa, Italy.
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Mingari
authors.affiliation: Pathology and Molecular Diagnostic Laboratory, Dept. of Service, IRCCS AOU San Martino-IST, Genoa, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Zupo
authors.affiliation: Pathology and Molecular Diagnostic Laboratory, Dept. of Service, IRCCS AOU San Martino-IST, Genoa, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Cutrona
authors.affiliation: Clinical Oncohematology, University of Genoa, Genoa, Italy.
authors.forename: Ivana
authors.initials: I
authors.lastname: Pierri
authors.affiliation: Clinic of Internal Medicine 3, Dept. of Hematology, IRCCS AOU San Martino-IST, Genoa, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Balleari
authors.affiliation: Section of Pharmacology, Dept. of Internal Medicine, Genoa, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Pattarozzi
authors.affiliation: Pathological Anatomy, Tumor Immunology Unit, Dept. of Science for Health Promotion and Maternal Infantile "G. D'Alessandro", Palermo, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Calvaruso
authors.affiliation: Pathological Anatomy, Tumor Immunology Unit, Dept. of Science for Health Promotion and Maternal Infantile "G. D'Alessandro", Palermo, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Tripodo
authors.affiliation: Direzione Scientifica IRCCS AOU San Martino-IST, Genoa, Italy.
authors.forename: Manlio
authors.initials: M
authors.lastname: Ferrarini
authors.affiliation: Transfer Gene Laboratory, IRCCS AOU San Martino-IST, Genoa, Italy daniela.detotero@istge.it daniela.detotero@hsanmartino.it.
authors.forename: Daniela
authors.initials: D
authors.lastname: de Totero
mesh_terms: D002478:Cells, Cultured; D018920:Coculture Techniques; D015870:Gene Expression; D017228:Hepatocyte Growth Factor / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics* / Q000378:metabolism; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism*; D009000:Monocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics* / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism
chemical_list: D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D050796:STAT3 Transcription Factor; D016753:Interleukin-10; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met